Stock Ticker

The diversity of CD8+ T cell dysfunction in cancer and viral infection

  • Kroemer, G., Chan, T. A., Eggermont, A. M. M. & Galluzzi, L. Immunosurveillance in clinical cancer management. CA Cancer J. Clin. 74, 187–202 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Berry, R., Watson, G. M., Jonjic, S., Degli-Esposti, M. A. & Rossjohn, J. Modulation of innate and adaptive immunity by cytomegaloviruses. Nat. Rev. Immunol. 20, 113–127 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lam, N., Lee, Y. & Farber, D. L. A guide to adaptive immune memory. Nat. Rev. Immunol. 24, 810–829 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pritykin, Y. et al. A unified atlas of CD8 T cell dysfunctional states in cancer and infection. Mol. Cell 81, 2477–2493.e10 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Naulaerts, S. et al. Multiomics and spatial mapping characterizes human CD8+ T cell states in cancer. Sci. Transl. Med. 15, eadd1016 (2023). This study uses comprehensive multi-omics and spatial mapping to differentiate canonical CD8+ T cell exhaustion from other hypofunctional CD8+ T cell states such as tolerization in human cancers.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wei, S. C., Duffy, C. R. & Allison, J. P. Fundamental mechanisms of immune checkpoint blockade therapy. Cancer Discov. 8, 1069–1086 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • McLane, L. M., Abdel-Hakeem, M. S. & Wherry, E. J. CD8 T cell exhaustion during chronic viral infection and cancer. Annu. Rev. Immunol. 37, 457–495 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chow, A., Perica, K., Klebanoff, C. A. & Wolchok, J. D. Clinical implications of T cell exhaustion for cancer immunotherapy. Nat. Rev. Clin. Oncol. 19, 775–790 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Collier, J. L., Weiss, S. A., Pauken, K. E., Sen, D. R. & Sharpe, A. H. Not-so-opposite ends of the spectrum: CD8+ T cell dysfunction across chronic infection, cancer and autoimmunity. Nat. Immunol. 22, 809–819 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bengsch, B. et al. Epigenomic-guided mass cytometry profiling reveals disease-specific features of exhausted CD8 T cells. Immunity 48, 1029–1045.e5 (2018). This study uses transcriptomic and epigenetic approaches to define core as well as disease-specific molecular features of T cell exhaustion in HIV and human cancers.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kinget, L. et al. A spatial architecture-embedding HLA signature to predict clinical response to immunotherapy in renal cell carcinoma. Nat. Med. 30, 1667–1679 (2024). This study reveals how spatially defined antigenic niches, enriching pre-exhausted and exhausted CD8+ T cells, distinguish immunotherapy responses in real-world patients with kidney cancer.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Borst, J., Ahrends, T., Bąbała, N., Melief, C. J. M. & Kastenmüller, W. CD4+ T cell help in cancer immunology and immunotherapy. Nat. Rev. Immunol. 18, 635–647 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chechlinska, M., Kowalewska, M. & Nowak, R. Systemic inflammation as a confounding factor in cancer biomarker discovery and validation. Nat. Rev. Cancer 10, 2–3 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wculek, S. K. et al. Dendritic cells in cancer immunology and immunotherapy. Nat. Rev. Immunol. 20, 7–24 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lei, X. et al. CD4+ helper T cells endow cDC1 with cancer-impeding functions in the human tumor micro-environment. Nat. Commun. 14, 217 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mempel, T. R., Lill, J. K. & Altenburger, L. M. How chemokines organize the tumour microenvironment. Nat. Rev. Cancer 24, 28–50 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Galluzzi, L. et al. Consensus guidelines for the definition, detection and interpretation of immunogenic cell death. J. Immunother. Cancer 8, e000337 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Propper, D. J. & Balkwill, F. R. Harnessing cytokines and chemokines for cancer therapy. Nat. Rev. Clin. Oncol. 19, 237–253 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, Y., Jiang, W. & Zhou, R. DAMP sensing and sterile inflammation: intracellular, intercellular and inter-organ pathways. Nat. Rev. Immunol. 24, 703–719 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yang, K., Halima, A. & Chan, T. A. Antigen presentation in cancer — mechanisms and clinical implications for immunotherapy. Nat. Rev. Clin. Oncol. 20, 604–623 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Takada, K. & Jameson, S. C. Naive T cell homeostasis: from awareness of space to a sense of place. Nat. Rev. Immunol. 9, 823–832 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • ElTanbouly, M. A. & Noelle, R. J. Rethinking peripheral T cell tolerance: checkpoints across a T cell’s journey. Nat. Rev. Immunol. 21, 257–267 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Brown, C. C. & Rudensky, A. Y. Spatiotemporal regulation of peripheral T cell tolerance. Science 380, 472–478 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Ashby, K. M. & Hogquist, K. A. A guide to thymic selection of T cells. Nat. Rev. Immunol. 24, 103–117 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Stern, L. J., Clement, C., Galluzzi, L. & Santambrogio, L. Non-mutational neoantigens in disease. Nat. Immunol. 25, 29–40 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tanchot, C. et al. Tumor-infiltrating regulatory T cells: phenotype, role, mechanism of expansion in situ and clinical significance. Cancer Microenviron. 6, 147–157 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Philip, M. & Schietinger, A. CD8+ T cell differentiation and dysfunction in cancer. Nat. Rev. Immunol. 22, 209–223 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Galluzzi, L., Chan, T. A., Kroemer, G., Wolchok, J. D. & López-Soto, A. The hallmarks of successful anticancer immunotherapy. Sci. Transl. Med. 10, eaat7807 (2018).

    Article 
    PubMed 

    Google Scholar
     

  • Galon, J. & Bruni, D. Approaches to treat immune hot, altered and cold tumours with combination immunotherapies. Nat. Rev. Drug Discov. 18, 197–218 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Galassi, C., Chan, T. A., Vitale, I. & Galluzzi, L. The hallmarks of cancer immune evasion. Cancer Cell 42, 1825–1863 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Golstein, P. & Griffiths, G. M. An early history of T cell-mediated cytotoxicity. Nat. Rev. Immunol. 18, 527–535 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vanderlugt, C. L. & Miller, S. D. Epitope spreading in immune-mediated diseases: implications for immunotherapy. Nat. Rev. Immunol. 2, 85–95 (2002).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Woodland, D. L. & Kohlmeier, J. E. Migration, maintenance and recall of memory T cells in peripheral tissues. Nat. Rev. Immunol. 9, 153–161 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Shakiba, M. et al. TCR signal strength defines distinct mechanisms of T cell dysfunction and cancer evasion. J. Exp. Med. 219, e20201966 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • van der Leun, A. M., Thommen, D. S. & Schumacher, T. N. CD8+ T cell states in human cancer: insights from single-cell analysis. Nat. Rev. Cancer 20, 218–232 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sullivan, B. M., Juedes, A., Szabo, S. J., von Herrath, M. & Glimcher, L. H. Antigen-driven effector CD8 T cell function regulated by T-bet. Proc. Natl Acad. Sci. USA 100, 15818–15823 (2003).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Weigelin, B. et al. Cytotoxic T cells are able to efficiently eliminate cancer cells by additive cytotoxicity. Nat. Commun. 12, 5217 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lee, K. P., Epstein, B., Lake, C. M. & Snow, A. L. Molecular and temporal control of restimulation-induced cell death (RICD) in T lymphocytes. Front. Cell Death 2, 1281137 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kaech, S. M. et al. Selective expression of the interleukin 7 receptor identifies effector CD8 T cells that give rise to long-lived memory cells. Nat. Immunol. 4, 1191–1198 (2003).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Youngblood, B. et al. Effector CD8 T cells dedifferentiate into long-lived memory cells. Nature 552, 404–409 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oliveira, G. & Wu, C. J. Dynamics and specificities of T cells in cancer immunotherapy. Nat. Rev. Cancer 23, 295–316 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vitale, I., Shema, E., Loi, S. & Galluzzi, L. Intratumoral heterogeneity in cancer progression and response to immunotherapy. Nat. Med. 27, 212–224 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zheng, L. et al. Pan-cancer single-cell landscape of tumor-infiltrating T cells. Science 374, abe6474 (2021).

    Article 
    PubMed 

    Google Scholar
     

  • Scott, A. C. et al. TOX is a critical regulator of tumour-specific T cell differentiation. Nature 571, 270–274 (2019). This study identifies the nuclear factor TOX as a key regulator of tumour-specific dysfunctional T cells as well as T cell exhaustion in the context of chronic viral infection.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sekine, T. et al. TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Sci. Immunol. 5, eaba7918 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Blank, C. U. et al. Defining ‘T cell exhaustion’. Nat. Rev. Immunol. 19, 665–674 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Philip, M. et al. Chromatin states define tumour-specific T cell dysfunction and reprogramming. Nature 545, 452–456 (2017). This study highlights two distinct chromatin states in tumoural T cells — a plastic dysfunctional state that can be rejuvenated and a fixed dysfunctional state that is irreversible.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Burger, M. L. et al. Antigen dominance hierarchies shape TCF1+ progenitor CD8 T cell phenotypes in tumors. Cell 184, 4996–5014.e26 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Utzschneider, D. T. et al. T cell factor 1-expressing memory-like CD8+ T cells sustain the immune response to chronic viral infections. Immunity 45, 415–427 (2016). This study is among the few early studies that document a TCF1+ stem-like T cell population that could have been a prime target for disease-resolving therapeutic interventions.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chen, Z. et al. TCF-1-centered transcriptional network drives an effector versus exhausted CD8 T cell-fate decision. Immunity 51, 840–855.e5 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gebhardt, T., Park, S. L. & Parish, I. A. Stem-like exhausted and memory CD8+ T cells in cancer. Nat. Rev. Cancer 23, 780–798 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Meiser, P. et al. A distinct stimulatory cDC1 subpopulation amplifies CD8+ T cell responses in tumors for protective anti-cancer immunity. Cancer Cell 41, 1498–1515.e10 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Siddiqui, I. et al. Intratumoral Tcf1+PD-1+CD8+ T cells with stem-like properties promote tumor control in response to vaccination and checkpoint blockade immunotherapy. Immunity 50, 195–211.e10 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016). This study documents the self-renewal and maintenance capacities of stem-like CD8+ T cells as well as their high sensitivity towards proliferative burst induced by PD1 blockade.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Leong, Y. A. et al. CXCR5+ follicular cytotoxic T cells control viral infection in B cell follicles. Nat. Immunol. 17, 1187–1196 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Levin, N. et al. Neoantigen-specific stimulation of tumor-infiltrating lymphocytes enables effective TCR isolation and expansion while preserving stem-like memory phenotypes. J. Immunother. Cancer 12, e008645 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Brummelman, J. et al. High-dimensional single cell analysis identifies stem-like cytotoxic CD8+ T cells infiltrating human tumors. J. Exp. Med. 215, 2520–2535 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kurtulus, S. et al. Checkpoint blockade immunotherapy induces dynamic changes in PD-1-CD8+ tumor-infiltrating T cells. Immunity 50, 181–194.e6 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Murgaski, A. et al. Efficacy of CD40 agonists is mediated by distinct cDC subsets and subverted by suppressive macrophages. Cancer Res. 82, 3785–3801 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hanna, B. S. et al. Interleukin-10 receptor signaling promotes the maintenance of a PD-1int TCF-1+CD8+ T cell population that sustains anti-tumor immunity. Immunity 54, 2825–2841.e10 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yao, C. et al. BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+ T cells. Nat. Immunol. 22, 370–380 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, Z. et al. In vivo CD8+ T cell CRISPR screening reveals control by Fli1 in infection and cancer. Cell 184, 1262–1280.e22 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beltra, J.-C. et al. Developmental relationships of four exhausted CD8+ T cell subsets reveals underlying transcriptional and epigenetic landscape control mechanisms. Immunity 52, 825–841.e8 (2020). This study uses molecular, transcriptional and epigenetic analyses to reveal a four-stage developmental hierarchy for exhausted T cells, coordinated by TCF1, T-bet and TOX.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Utzschneider, D. T. et al. Early precursor T cells establish and propagate T cell exhaustion in chronic infection. Nat. Immunol. 21, 1256–1266 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Huang, Q. et al. The primordial differentiation of tumor-specific memory CD8+ T cells as bona fide responders to PD-1/PD-L1 blockade in draining lymph nodes. Cell 185, 4049–4066.e25 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Connolly, K. A. et al. A reservoir of stem-like CD8+ T cells in the tumor-draining lymph node preserves the ongoing antitumor immune response. Sci. Immunol. 6, eabg7836 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Borràs, D. M. et al. Single cell dynamics of tumor specificity vs bystander activity in CD8+ T cells define the diverse immune landscapes in colorectal cancer. Cell Discov. 9, 114 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Gill, A. L. et al. PD-1 blockade increases the self-renewal of stem-like CD8 T cells to compensate for their accelerated differentiation into effectors. Sci. Immunol. 8, eadg0539 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Miller, B. C. et al. Subsets of exhausted CD8+ T cells differentially mediate tumor control and respond to checkpoint blockade. Nat. Immunol. 20, 326–336 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Utzschneider, D. T. et al. High antigen levels induce an exhausted phenotype in a chronic infection without impairing T cell expansion and survival. J. Exp. Med. 213, 1819–1834 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ghorani, E. et al. The T cell differentiation landscape is shaped by tumour mutations in lung cancer. Nat. Cancer 1, 546–561 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hu, Y. et al. TGF-β regulates the stem-like state of PD-1+TCF-1+ virus-specific CD8 T cells during chronic infection. J. Exp. Med. 219, e20211574 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Marx, A.-F. et al. The alarmin interleukin-33 promotes the expansion and preserves the stemness of Tcf-1+CD8+ T cells in chronic viral infection. Immunity 56, 813–828.e10 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gabriel, S. S. et al. Transforming growth factor-β-regulated mTOR activity preserves cellular metabolism to maintain long-term T cell responses in chronic infection. Immunity 54, 1698–1714.e5 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vardhana, S. A. et al. Impaired mitochondrial oxidative phosphorylation limits the self-renewal of T cells exposed to persistent antigen. Nat. Immunol. 21, 1022–1033 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zander, R. et al. CD4+ T cell help is required for the formation of a cytolytic CD8+ T cell subset that protects against chronic infection and cancer. Immunity 51, 1028–1042.e4 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cui, C. et al. Neoantigen-driven B cell and CD4 T follicular helper cell collaboration promotes anti-tumor CD8 T cell responses. Cell 184, 6101–6118.e13 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Beltra, J.-C. et al. IL2Rβ-dependent signals drive terminal exhaustion and suppress memory development during chronic viral infection. Proc. Natl Acad. Sci. USA 113, E5444–E5453 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wu, T. et al. The TCF1–Bcl6 axis counteracts type I interferon to repress exhaustion and maintain T cell stemness. Sci. Immunol. 1, eaai8593 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lukhele, S. et al. The transcription factor IRF2 drives interferon-mediated CD8+ T cell exhaustion to restrict anti-tumor immunity. Immunity 55, 2369–2385.e10 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Acharya, N. et al. Endogenous glucocorticoid signaling regulates CD8+ T cell differentiation and development of dysfunction in the tumor microenvironment. Immunity 53, 658–671.e6 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sun, Q. et al. BCL6 promotes a stem-like CD8+ T cell program in cancer via antagonizing BLIMP1. Sci. Immunol. 8, eadh1306 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lacher, S. B. et al. PGE2 limits effector expansion of tumour-infiltrating stem-like CD8+ T cells. Nature 629, 417–425 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sprooten, J. et al. Lymph node and tumor-associated PD-L1+ macrophages antagonize dendritic cell vaccines by suppressing CD8+ T cells. Cell Rep. Med. 5, 101377 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Khan, O. et al. TOX transcriptionally and epigenetically programs CD8+ T cell exhaustion. Nature 571, 211–218 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Alfei, F. et al. TOX reinforces the phenotype and longevity of exhausted T cells in chronic viral infection. Nature 571, 265–269 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Buggert, M. et al. T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection. PLoS Pathog. 10, e1004251 (2014).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jin, H.-T. et al. Cooperation of Tim-3 and PD-1 in CD8 T-cell exhaustion during chronic viral infection. Proc. Natl Acad. Sci. USA 107, 14733–14738 (2010).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Johnston, R. J. et al. The immunoreceptor TIGIT regulates antitumor and antiviral CD8+ T cell effector function. Cancer Cell 26, 923–937 (2014).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vignali, P. D. A. et al. Hypoxia drives CD39-dependent suppressor function in exhausted T cells to limit antitumor immunity. Nat. Immunol. 24, 267–279 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zhang, Z. et al. Pan-cancer landscape of T-cell exhaustion heterogeneity within the tumor microenvironment revealed a progressive roadmap of hierarchical dysfunction associated with prognosis and therapeutic efficacy. EBioMedicine 83, 104207 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Martinez, G. J. et al. The transcription factor NFAT promotes exhaustion of activated CD8+ T cells. Immunity 42, 265–278 (2015).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Curdy, N., Lanvin, O., Laurent, C., Fournié, J.-J. & Franchini, D.-M. Regulatory mechanisms of inhibitory immune checkpoint receptors expression. Trends Cell Biol. 29, 777–790 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hashimoto, M. et al. CD8 T cell exhaustion in chronic infection and cancer: opportunities for interventions. Annu. Rev. Med. 69, 301–318 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Peralta, R. M. et al. Dysfunction of exhausted T cells is enforced by MCT11-mediated lactate metabolism. Nat. Immunol. 25, 2297–2307 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scharping, N. E. et al. Mitochondrial stress induced by continuous stimulation under hypoxia rapidly drives T cell exhaustion. Nat. Immunol. 22, 205–215 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wang, C. et al. Circadian tumor infiltration and function of CD8+ T cells dictate immunotherapy efficacy. Cell 187, 2690–2702.e17 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bader, J. E. et al. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity. Nature 630, 968–975 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gallerano, D. et al. Genetically driven CD39 expression shapes human tumor-infiltrating CD8+ T-cell functions. Int. J. Cancer 147, 2597–2610 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Baessler, A. & Vignali, D. A. A. T cell exhaustion. Annu. Rev. Immunol. 42, 179–206 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chalabi, M. et al. Neoadjuvant immunotherapy leads to pathological responses in MMR-proficient and MMR-deficient early-stage colon cancers. Nat. Med. 26, 566–576 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Abdel-Hakeem, M. S. et al. Epigenetic scarring of exhausted T cells hinders memory differentiation upon eliminating chronic antigenic stimulation. Nat. Immunol. 22, 1008–1019 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yates, K. B. et al. Epigenetic scars of CD8+ T cell exhaustion persist after cure of chronic infection in humans. Nat. Immunol. 22, 1020–1029 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Meier, S. L., Satpathy, A. T. & Wells, D. K. Bystander T cells in cancer immunology and therapy. Nat. Cancer 3, 143–155 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Lee, H., Jeong, S. & Shin, E.-C. Significance of bystander T cell activation in microbial infection. Nat. Immunol. 23, 13–22 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Li, B. et al. Landscape of tumor-infiltrating T cell repertoire of human cancers. Nat. Genet. 48, 725–732 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Caushi, J. X. et al. Transcriptional programs of neoantigen-specific TIL in anti-PD-1-treated lung cancers. Nature 596, 126–132 (2021). This study uses functional and transcriptomic analyses to differentiate neoantigen-specific T cells from virus-specific bystander T cells in during neoadjuvant PD1 blockade in patients with lung cancer.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Oliveira, G. et al. Phenotype, specificity and avidity of antitumour CD8+ T cells in melanoma. Nature 596, 119–125 (2021). This study shows how the cellular phenotype of tumoural T cells and the antigenic specificity of their TCRs together shape immunotherapy responsiveness in patients with melanoma.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Maurice, N. J., Taber, A. K. & Prlic, M. The ugly duckling turned to swan: a change in perception of bystander-activated memory CD8 T cells. J. Immunol. 206, 455–462 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Low, J. S. et al. Tissue-resident memory T cell reactivation by diverse antigen-presenting cells imparts distinct functional responses. J. Exp. Med. 217, e20192291 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Steinbach, P. et al. Influenza virus infection enhances tumour-specific CD8+ T-cell immunity, facilitating tumour control. PLoS Pathog. 20, e1011982 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Le, C. T. et al. Regulation of human and mouse bystander T cell activation responses by PD-1. JCI Insight 8, e173287 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Isaacs, J. F. et al. CD39 is expressed on functional effector and tissue-resident memory CD8+ T cells. J. Immunol. 213, 588–599 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Simoni, Y. et al. Bystander CD8+ T cells are abundant and phenotypically distinct in human tumour infiltrates. Nature 557, 575–579 (2018). A study that comprehensively highlights the underappreciated molecular role and immunological impact of bystander CD8+ T cells in human cancers.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gavil, N. V. et al. Chronic antigen in solid tumors drives a distinct program of T cell residence. Sci. Immunol. 8, eadd5976 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mognol, G. P. et al. Exhaustion-associated regulatory regions in CD8+ tumor-infiltrating T cells. Proc. Natl Acad. Sci. USA 114, E2776–E2785 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, X. et al. An oncolytic virus delivering tumor-irrelevant bystander T cell epitopes induces anti-tumor immunity and potentiates cancer immunotherapy. Nat. Cancer 5, 1063–1081 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Goebeler, M.-E., Stuhler, G. & Bargou, R. Bispecific and multispecific antibodies in oncology: opportunities and challenges. Nat. Rev. Clin. Oncol. 21, 539–560 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Rosato, P. C. et al. Virus-specific memory T cells populate tumors and can be repurposed for tumor immunotherapy. Nat. Commun. 10, 567 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nüssing, S., Trapani, J. A. & Parish, I. A. Revisiting T cell tolerance as a checkpoint target for cancer immunotherapy. Front. Immunol. 11, 589641 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zehn, D. & Bevan, M. J. T cells with low avidity for a tissue-restricted antigen routinely evade central and peripheral tolerance and cause autoimmunity. Immunity 25, 261–270 (2006).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bouneaud, C., Kourilsky, P. & Bousso, P. Impact of negative selection on the T cell repertoire reactive to a self-peptide: a large fraction of T cell clones escapes clonal deletion. Immunity 13, 829–840 (2000).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hernandez, J., Aung, S., Redmond, W. L. & Sherman, L. A. Phenotypic and functional analysis of CD8+ T cells undergoing peripheral deletion in response to cross-presentation of self-antigen. J. Exp. Med. 194, 707–717 (2001).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Redmond, W. L. & Sherman, L. A. Peripheral tolerance of CD8 T lymphocytes. Immunity 22, 275–284 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Schietinger, A., Delrow, J. J., Basom, R. S., Blattman, J. N. & Greenberg, P. D. Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state. Science 335, 723–727 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Van Der Byl, W. et al. The CD8+ T cell tolerance checkpoint triggers a distinct differentiation state defined by protein translation defects. Immunity 57, 1324–1344.e8 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Rivoltini, L. et al. Induction of tumor-reactive CTL from peripheral blood and tumor-infiltrating lymphocytes of melanoma patients by in vitro stimulation with an immunodominant peptide of the human melanoma antigen MART-1. J. Immunol. 154, 2257–2265 (1995).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Coulie, P. G. et al. A new gene coding for a differentiation antigen recognized by autologous cytolytic T lymphocytes on HLA-A2 melanomas. J. Exp. Med. 180, 35–42 (1994).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lund, A. W. et al. VEGF-C promotes immune tolerance in B16 melanomas and cross-presentation of tumor antigen by lymph node lymphatics. Cell Rep. 1, 191–199 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Bai, A., Higham, E., Eisen, H. N., Wittrup, K. D. & Chen, J. Rapid tolerization of virus-activated tumor-specific CD8+ T cells in prostate tumors of TRAMP mice. Proc. Natl Acad. Sci. USA 105, 13003–13008 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Teague, R. M. et al. Peripheral CD8+ T cell tolerance to self-proteins is regulated proximally at the T cell receptor. Immunity 28, 662–674 (2008).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Woroniecka, K. et al. T-cell exhaustion signatures vary with tumor type and are severe in glioblastoma. Clin. Cancer Res. 24, 4175–4186 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Damo, M. et al. PD-1 maintains CD8 T cell tolerance towards cutaneous neoantigens. Nature 619, 151–159 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nelson, C. E. et al. Reprogramming responsiveness to checkpoint blockade in dysfunctional CD8 T cells. Proc. Natl Acad. Sci. USA 116, 2640–2645 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Nelson, C. E. et al. Robust iterative stimulation with self-antigens overcomes CD8+ T cell tolerance to self- and tumor antigens. Cell Rep. 28, 3092–3104.e5 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zehn, D., Lee, S. Y. & Bevan, M. J. Complete but curtailed T-cell response to very low-affinity antigen. Nature 458, 211–214 (2009).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Shimizu, K. et al. PD-1 preferentially inhibits the activation of low-affinity T cells. Proc. Natl Acad. Sci. USA 118, e2107141118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mattila, J. et al. Analysis of thymic generation of shared T-cell receptor α repertoire associated with recognition of tumor antigens shows no preference for neoantigens over wild-type antigens. Cancer Med. 12, 13486–13496 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Komuro, H. et al. Single-cell sequencing on CD8+ TILs revealed the nature of exhausted T cells recognizing neoantigen and cancer/testis antigen in non-small cell lung cancer. J. Immunother. Cancer 11, e007180 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Black, C. M., Armstrong, T. D. & Jaffee, E. M. Apoptosis-regulated low-avidity cancer-specific CD8+ T cells can be rescued to eliminate HER2/neu-expressing tumors by costimulatory agonists in tolerized mice. Cancer Immunol. Res. 2, 307–319 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Li, S. et al. Characterization of neoantigen-specific T cells in cancer resistant to immune checkpoint therapies. Proc. Natl Acad. Sci. USA 118, e2025570118 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mi, T. et al. Conserved epigenetic hallmarks of T cell aging during immunity and malignancy. Nat. Aging 4, 1053–1063 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Quinn, K. M. et al. Age-related decline in primary CD8+ T cell responses is associated with the development of senescence in virtual memory CD8+ T cells. Cell Rep. 23, 3512–3524 (2018).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, X. et al. Regulatory T cells trigger effector T cell DNA damage and senescence caused by metabolic competition. Nat. Commun. 9, 249 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Strioga, M., Pasukoniene, V. & Characiejus, D. CD8+CD28 and CD8+CD57+ T cells and their role in health and disease. Immunology 134, 17–32 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vallejo, A. N. CD28 extinction in human T cells: altered functions and the program of T-cell senescence. Immunol. Rev. 205, 158–169 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Koh, J.-Y., Kim, D.-U., Moon, B.-H. & Shin, E.-C. Human CD8+ T-cell populations that express natural killer receptors. Immune Netw. 23, e8 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Ahuja, S. K. et al. Immune resilience despite inflammatory stress promotes longevity and favorable health outcomes including resistance to infection. Nat. Commun. 14, 3286 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Soerens, A. G. et al. Functional T cells are capable of supernumerary cell division and longevity. Nature 614, 762–766 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Galluzzi, L. et al. Molecular mechanisms of cell death: recommendations of the Nomenclature Committee on Cell Death 2018. Cell Death Differ. 25, 486–541 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chu, Y. et al. Pan-cancer T cell atlas links a cellular stress response state to immunotherapy resistance. Nat. Med. 29, 1550–1562 (2023). A study that comprehensively highlights the underappreciated enrichment of stressed or dying T cells in human cancers and their negative impact on immunotherapy responsiveness.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • DePeaux, K. & Delgoffe, G. M. Metabolic barriers to cancer immunotherapy. Nat. Rev. Immunol. 21, 785–797 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sanmamed, M. F. et al. A burned-out CD8+ T-cell subset expands in the tumor microenvironment and curbs cancer immunotherapy. Cancer Discov. 11, 1700–1715 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhu, J. et al. Resistance to cancer immunotherapy mediated by apoptosis of tumor-infiltrating lymphocytes. Nat. Commun. 8, 1404 (2017).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Janssen, E. M. et al. CD4+ T-cell help controls CD8+ T-cell memory via TRAIL-mediated activation-induced cell death. Nature 434, 88–93 (2005).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Motz, G. T. et al. Tumor endothelium FasL establishes a selective immune barrier promoting tolerance in tumors. Nat. Med. 20, 607–615 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wolkers, M. C., Bensinger, S. J., Green, D. R., Schoenberger, S. P. & Janssen, E. M. Interleukin-2 rescues helpless effector CD8+ T cells by diminishing the susceptibility to TRAIL mediated death. Immunol. Lett. 139, 25–32 (2011).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Morotti, M. et al. PGE2 inhibits TIL expansion by disrupting IL-2 signalling and mitochondrial function. Nature 629, 426–434 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cullen, J. G. et al. CD4+ T help promotes influenza virus-specific CD8+ T cell memory by limiting metabolic dysfunction. Proc. Natl Acad. Sci. USA 116, 4481–4488 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hashimoto, M. et al. PD-1 combination therapy with IL-2 modifies CD8+ T cell exhaustion program. Nature 610, 173–181 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pai, C.-C. S. et al. Clonal deletion of tumor-specific T cells by interferon-γ confers therapeutic resistance to combination immune checkpoint blockade. Immunity 50, 477–492.e8 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hailemichael, Y. et al. Persistent antigen at vaccination sites induces tumor-specific CD8+ T cell sequestration, dysfunction and deletion. Nat. Med. 19, 465–472 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schenkel, J. M. & Pauken, K. E. Localization, tissue biology and T cell state — implications for cancer immunotherapy. Nat. Rev. Immunol. 23, 807–823 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zenke, S. et al. Quorum Regulation via nested antagonistic feedback circuits mediated by the receptors CD28 and CTLA-4 confers robustness to T cell population dynamics. Immunity 52, 313–327.e7 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Roberts, A. D. & Woodland, D. L. Cutting edge: effector memory CD8+ T cells play a prominent role in recall responses to secondary viral infection in the lung. J. Immunol. 172, 6533–6537 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Vanderbeke, L. et al. Monocyte-driven atypical cytokine storm and aberrant neutrophil activation as key mediators of COVID-19 disease severity. Nat. Commun. 12, 4117 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wauters, E. et al. Discriminating mild from critical COVID-19 by innate and adaptive immune single-cell profiling of bronchoalveolar lavages. Cell Res. 31, 272–290 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rodríguez-Ubreva, J. et al. COVID-19 progression and convalescence in common variable immunodeficiency patients show dysregulated adaptive immune responses and persistent type I interferon and inflammasome activation. Nat. Commun. 15, 10344 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chu, T. et al. Precursors of exhausted T cells are preemptively formed in acute infection. Nature, https://doi.org/10.1038/s41586-024-08451-4 (2025).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • McManus, D. T. et al. An early precursor CD8 T cell that adapts to acute or chronic viral infection. Nature, https://doi.org/10.1038/41586-024-08562-y (2025).

    Article 
    PubMed 

    Google Scholar
     

  • Jadhav, R. R. et al. Epigenetic signature of PD-1+TCF1+CD8 T cells that act as resource cells during chronic viral infection and respond to PD-1 blockade. Proc. Natl Acad. Sci. USA 116, 14113–14118 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kanev, K. & Zehn, D. Origin and fine-tuning of effector CD8 T cell subpopulations in chronic infection. Curr. Opin. Virol. 46, 27–35 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Hoffmann, M. et al. Exhaustion of activated CD8 T cells predicts disease progression in primary HIV-1 infection. PLoS Pathog. 12, e1005661 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Wherry, E. J. et al. Molecular signature of CD8+ T cell exhaustion during chronic viral infection. Immunity 27, 670–684 (2007).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Holder, A. M. et al. Defining clinically useful biomarkers of immune checkpoint inhibitors in solid tumours. Nat. Rev. Cancer 24, 498–512 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Anagnostou, V., Bardelli, A., Chan, T. A. & Turajlic, S. The status of tumor mutational burden and immunotherapy. Nat. Cancer 3, 652–656 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Łuksza, M. et al. Neoantigen quality predicts immunoediting in survivors of pancreatic cancer. Nature 606, 389–395 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scheper, W. et al. Low and variable tumor reactivity of the intratumoral TCR repertoire in human cancers. Nat. Med. 25, 89–94 (2019). This study highlights that actionable tumour-specific T cells are relatively rare and variable, thereby highlighting the need to balance T cell quantity versus quality during immunotherapy.

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Verdegaal, E. M. E. et al. Neoantigen landscape dynamics during human melanoma–T cell interactions. Nature 536, 91–95 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Valpione, S. et al. The T cell receptor repertoire of tumor infiltrating T cells is predictive and prognostic for cancer survival. Nat. Commun. 12, 4098 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, P. et al. Single-cell CRISPR screens in vivo map T cell fate regulomes in cancer. Nature 624, 154–163 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Westcott, P. M. K. et al. Mismatch repair deficiency is not sufficient to elicit tumor immunogenicity. Nat. Genet. 55, 1686–1695 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Spranger, S., Bao, R. & Gajewski, T. F. Melanoma-intrinsic β-catenin signalling prevents anti-tumour immunity. Nature 523, 231–235 (2015).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Wu, S. et al. The antitumor effects of vaccine-activated CD8+ T cells associate with weak TCR signaling and induction of stem-like memory T cells. Cancer Immunol. Res. 5, 908–919 (2017).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Waldman, A. D., Fritz, J. M. & Lenardo, M. J. A guide to cancer immunotherapy: from T cell basic science to clinical practice. Nat. Rev. Immunol. 20, 651–668 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lopez de Rodas, M. & Schalper, K. A. Tumour antigen-induced T cell exhaustion — the archenemy of immune-hot malignancies. Nat. Rev. Clin. Oncol. 18, 749–750 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Westcott, P. M. K. et al. Low neoantigen expression and poor T-cell priming underlie early immune escape in colorectal cancer. Nat. Cancer 2, 1071–1085 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Lu, K. H.-N. et al. T cell receptor dynamic and transcriptional determinants of T cell expansion in glioma-infiltrating T cells. Neurooncol. Adv. 4, vdac140 (2022).

    PubMed 
    PubMed Central 

    Google Scholar
     

  • Agudo, J. & Miao, Y. Stemness in solid malignancies: coping with immune attack. Nat. Rev. Cancer 25, 27–40 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Swanton, C. et al. Embracing cancer complexity: hallmarks of systemic disease. Cell 187, 1589–1616 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Khalili, J. S. et al. Oncogenic BRAF(V600E) promotes stromal cell-mediated immunosuppression via induction of interleukin-1 in melanoma. Clin. Cancer Res. 18, 5329–5340 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peng, W. et al. Loss of PTEN promotes resistance to T cell-mediated immunotherapy. Cancer Discov. 6, 202–216 (2016).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pan, D. et al. A major chromatin regulator determines resistance of tumor cells to T cell-mediated killing. Science 359, 770–775 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roelands, J. et al. Oncogenic states dictate the prognostic and predictive connotations of intratumoral immune response. J. Immunother. Cancer 8, e000617 (2020).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kumagai, S. et al. An oncogenic alteration creates a microenvironment that promotes tumor progression by conferring a metabolic advantage to regulatory T cells. Immunity 53, 187–203.e8 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tsakonas, G. & Ekman, S. Oncogene-addicted non-small cell lung cancer and immunotherapy. J. Thorac. Dis. 10, S1547–S1555 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Coulton, A. et al. Using a pan-cancer atlas to investigate tumour associated macrophages as regulators of immunotherapy response. Nat. Commun. 15, 5665 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Luo, H. et al. Pan-cancer single-cell analysis reveals the heterogeneity and plasticity of cancer-associated fibroblasts in the tumor microenvironment. Nat. Commun. 13, 6619 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Pan, X. et al. Tumour vasculature at single-cell resolution. Nature 632, 429–436 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Takahashi, M. et al. Intratumoral antigen signaling traps CD8+ T cells to confine exhaustion to the tumor site. Sci. Immunol. 9, eade2094 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hua, Y. et al. Cancer immunotherapies transition endothelial cells into HEVs that generate TCF1+ T lymphocyte niches through a feed-forward loop. Cancer Cell 41, 226 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • de Visser, K. E. & Joyce, J. A. The evolving tumor microenvironment: from cancer initiation to metastatic outgrowth. Cancer Cell 41, 374–403 (2023).

    Article 
    PubMed 

    Google Scholar
     

  • Im, S. J. et al. Characteristics and anatomic location of PD-1+TCF1+ stem-like CD8 T cells in chronic viral infection and cancer. Proc. Natl Acad. Sci. USA 120, e2221985120 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Espinosa-Carrasco, G. et al. Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors. Cancer Cell 42, 1202–1216.e8 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Magen, A. et al. Intratumoral dendritic cell-CD4+ T helper cell niches enable CD8+ T cell differentiation following PD-1 blockade in hepatocellular carcinoma. Nat. Med. 29, 1389–1399 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bala, N. et al. T cell activation niches-optimizing T cell effector function in inflamed and infected tissues. Immunol. Rev. 306, 164–180 (2022).

    Article 
    PubMed 

    Google Scholar
     

  • Pelka, K. et al. Spatially organized multicellular immune hubs in human colorectal cancer. Cell 184, 4734–4752.e20 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Jansen, C. S. et al. An intra-tumoral niche maintains and differentiates stem-like CD8 T cells. Nature 576, 465–470 (2019). This is among some early studies that highlight a role for spatial niches that enrich stem-like T cells within the tumours as key regulators of T cell infiltration and patient prognosis.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Di Pilato, M. et al. CXCR6 positions cytotoxic T cells to receive critical survival signals in the tumor microenvironment. Cell 184, 4512–4530.e22 (2021).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Chen, J. H. et al. Human lung cancer harbors spatially organized stem-immunity hubs associated with response to immunotherapy. Nat. Immunol. 25, 644–658 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Gaglia, G. et al. Lymphocyte networks are dynamic cellular communities in the immunoregulatory landscape of lung adenocarcinoma. Cancer Cell 41, 871–886.e10 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kasikova, L. et al. Tertiary lymphoid structures and B cells determine clinically relevant T cell phenotypes in ovarian cancer. Nat. Commun. 15, 2528 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Hoch, T. et al. Multiplexed imaging mass cytometry of the chemokine milieus in melanoma characterizes features of the response to immunotherapy. Sci. Immunol. 7, eabk1692 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Lynch, K. T. et al. Heterogeneity in tertiary lymphoid structure B-cells correlates with patient survival in metastatic melanoma. J. Immunother. Cancer 9, e000617 (2021).

    Article 

    Google Scholar
     

  • Helmink, B. A. et al. B cells and tertiary lymphoid structures promote immunotherapy response. Nature 577, 549–555 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Cabrita, R. et al. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature 577, 561–565 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Petitprez, F. et al. B cells are associated with survival and immunotherapy response in sarcoma. Nature 577, 556–560 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Rahim, M. K. et al. Dynamic CD8+ T cell responses to cancer immunotherapy in human regional lymph nodes are disrupted in metastatic lymph nodes. Cell 186, 1127–1143.e18 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Opzoomer, J. W. et al. Macrophages orchestrate the expansion of a proangiogenic perivascular niche during cancer progression. Sci. Adv. 7, eabg9518 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Eil, R. et al. Ionic immune suppression within the tumour microenvironment limits T cell effector function. Nature 537, 539–543 (2016).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vodnala, S. K. et al. T cell stemness and dysfunction in tumors are triggered by a common mechanism. Science 363, eaau0135 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • De Martino, M., Rathmell, J. C., Galluzzi, L. & Vanpouille-Box, C. Cancer cell metabolism and antitumour immunity. Nat. Rev. Immunol. 24, 654–669 (2024).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tumeh, P. C. et al. PD-1 blockade induces responses by inhibiting adaptive immune resistance. Nature 515, 568–571 (2014).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Scolaro, T. et al. Nucleotide metabolism in cancer cells fuels a UDP-driven macrophage cross-talk, promoting immunosuppression and immunotherapy resistance. Nat. Cancer 5, 1206–1226 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vanmeerbeek, I. et al. Targeting conserved TIM3+VISTA+ tumor-associated macrophages overcomes resistance to cancer immunotherapy. Sci. Adv. 10, eadm8660 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Xiao, Z. et al. Desmoplastic stroma restricts T cell extravasation and mediates immune exclusion and immunosuppression in solid tumors. Nat. Commun. 14, 5110 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Peranzoni, E. et al. Macrophages impede CD8 T cells from reaching tumor cells and limit the efficacy of anti-PD-1 treatment. Proc. Natl Acad. Sci. USA 115, E4041–E4050 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhang, J. et al. Osr2 functions as a biomechanical checkpoint to aggravate CD8+ T cell exhaustion in tumor. Cell 187, 3409–3426.e24 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yu, J. et al. Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination. Nat. Med. 27, 152–164 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Desbois, M. et al. Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nat. Commun. 11, 5583 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Grout, J. A. et al. Spatial positioning and matrix programs of cancer-associated fibroblasts promote T-cell exclusion in human lung tumors. Cancer Discov. 12, 2606–2625 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Park, H.-R. et al. Angiopoietin-2-dependent spatial vascular destabilization promotes T-cell exclusion and limits immunotherapy in melanoma. Cancer Res. 83, 1968–1983 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Croizer, H. et al. Deciphering the spatial landscape and plasticity of immunosuppressive fibroblasts in breast cancer. Nat. Commun. 15, 2806 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yang, F. et al. An immunosuppressive vascular niche drives macrophage polarization and immunotherapy resistance in glioblastoma. Sci. Adv. 10, eadj4678 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sussman, J. H. et al. Multiplexed imaging mass cytometry analysis characterizes the vascular niche in pancreatic cancer. Cancer Res. 84, 2364–2376 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kinker, G. S. et al. Mature tertiary lymphoid structures are key niches of tumour-specific immune responses in pancreatic ductal adenocarcinomas. Gut 72, 1927–1941 (2023).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Maleki Vareki, S. High and low mutational burden tumors versus immunologically hot and cold tumors and response to immune checkpoint inhibitors. J. Immunother. Cancer 6, 157 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Litchfield, K. et al. Meta-analysis of tumor- and T cell-intrinsic mechanisms of sensitization to checkpoint inhibition. Cell 184, 596–614.e14 (2021).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Laureano, R. S. et al. The cell stress and immunity cycle in cancer: toward next generation of cancer immunotherapy. Immunol. Rev. 321, 71–93 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cloughesy, T. F. et al. Neoadjuvant anti-PD-1 immunotherapy promotes a survival benefit with intratumoral and systemic immune responses in recurrent glioblastoma. Nat. Med. 25, 477–486 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Schalper, K. A. et al. Neoadjuvant nivolumab modifies the tumor immune microenvironment in resectable glioblastoma. Nat. Med. 25, 470–476 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Randall, L. M. et al. Niraparib and dostarlimab for the treatment of recurrent platinum-resistant ovarian cancer: results of a Phase II study (MOONSTONE/GOG-3032). Gynecol. Oncol. 178, 161–169 (2023).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Mosalem, O. et al. A real-world experience of pembrolizumab monotherapy in microsatellite instability-high and/or tumor mutation burden-high metastatic castration-resistant prostate cancer: outcome analysis. Prostate Cancer Prostatic Dis. 28, 138–144 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Fabian, K. P., Padget, M. R., Fujii, R., Schlom, J. & Hodge, J. W. Differential combination immunotherapy requirements for inflamed (warm) tumors versus T cell excluded (cool) tumors: engage, expand, enable, and evolve. J. Immunotherapy. Cancer 9, e001691 (2021).

    Article 

    Google Scholar
     

  • Sayour, E. J., Boczkowski, D., Mitchell, D. A. & Nair, S. K. Cancer mRNA vaccines: clinical advances and future opportunities. Nat. Rev. Clin. Oncol. 21, 489–500 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Hensler, M. et al. Peripheral gene signatures reveal distinct cancer patient immunotypes with therapeutic implications for autologous DC-based vaccines. Oncoimmunology 11, 2101596 (2022).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Bashor, C. J., Hilton, I. B., Bandukwala, H., Smith, D. M. & Veiseh, O. Engineering the next generation of cell-based therapeutics. Nat. Rev. Drug. Discov. 21, 655–675 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Escobar, G., Mangani, D. & Anderson, A. C. T cell factor 1: a master regulator of the T cell response in disease. Sci. Immunol. 5, eabb9726 (2020).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Huff, W. X., Kwon, J. H., Henriquez, M., Fetcko, K. & Dey, M. The evolving role of CD8+CD28 immunosenescent T cells in cancer immunology. Int. J. Mol. Sci. 20, 2810 (2019).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zebley, C. C., Zehn, D., Gottschalk, S. & Chi, H. T cell dysfunction and therapeutic intervention in cancer. Nat. Immunol. 25, 1344–1354 (2024).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Thommen, D. S. & Schumacher, T. N. T cell dysfunction in cancer. Cancer Cell 33, 547–562 (2018).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Crespo, J., Sun, H., Welling, T. H., Tian, Z. & Zou, W. T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment. Curr. Opin. Immunol. 25, 214–221 (2013).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Rodríguez-Rodríguez, N., Rosetti, F. & Crispín, J. C. CD8 is down(regulated) for tolerance. Trends Immunol. 45, 442–453 (2024).

    Article 
    PubMed 

    Google Scholar
     

  • Luoma, A. M. et al. Tissue-resident memory and circulating T cells are early responders to pre-surgical cancer immunotherapy. Cell 185, 2918–2935.e29 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Yost, K. E. et al. Clonal replacement of tumor-specific T cells following PD-1 blockade. Nat. Med. 25, 1251–1259 (2019). This study highlights a key role of intratumoural T cell clonal replacement from extratumoural, peritumoural or tumour margins in regulating immunotherapy responsiveness.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Zhou, W. et al. Stem-like progenitor and terminally differentiated TFH-like CD4+ T cell exhaustion in the tumor microenvironment. Cell Rep. 43, 113797 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tooley, K. A., Escobar, G. & Anderson, A. C. Spatial determinants of CD8+ T cell differentiation in cancer. Trends Cancer 8, 642–654 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Sade-Feldman, M. et al. Defining T cell states associated with response to checkpoint immunotherapy in melanoma. Cell 175, 998–1013.e20 (2018). This is one of the early studies that used single-cell omics to reveal the positioning of different T cell states within patients with melanoma who responded or remained resistant to immunotherapy.

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Duhen, T. et al. Co-expression of CD39 and CD103 identifies tumor-reactive CD8 T cells in human solid tumors. Nat. Commun. 9, 2724 (2018).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Vick, L. V. et al. PD-1 signaling serves a dual role in suppressing T cell activation but also in protecting from activation-induced cell death. J. Immunol. 210, 226.11 (2023).

    Article 

    Google Scholar
     

  • Vanmeerbeek, I. et al. Early memory differentiation and cell death resistance in T cells predicts melanoma response to sequential anti-CTLA4 and anti-PD1 immunotherapy. Genes. Immun. 22, 108–119 (2021).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Dyikanov, D. et al. Comprehensive peripheral blood immunoprofiling reveals five immunotypes with immunotherapy response characteristics in patients with cancer. Cancer Cell 42, 759–779.e12 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Liu, B. et al. Temporal single-cell tracing reveals clonal revival and expansion of precursor exhausted T cells during anti-PD-1 therapy in lung cancer. Nat. Cancer 3, 108–121 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Cascone, T. et al. Perioperative nivolumab in resectable lung cancer. N. Engl. J. Med. 390, 1756–1769 (2024).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Larkin, J. et al. Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 373, 23–34 (2015).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Tawbi, H. A. et al. Relatlimab and nivolumab versus nivolumab in untreated advanced melanoma. N. Engl. J. Med. 386, 24–34 (2022).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Serritella, A. V. & Shenoy, N. K. Nivolumab plus ipilimumab vs nivolumab alone in advanced cancers other than melanoma: a meta-analysis. JAMA Oncol. 9, 1441–1446 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Voorwerk, L. et al. Immune induction strategies in metastatic triple-negative breast cancer to enhance the sensitivity to PD-1 blockade: the TONIC trial. Nat. Med. 25, 920–928 (2019).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Yokosuka, T. et al. Spatiotemporal basis of CTLA-4 costimulatory molecule-mediated negative regulation of T cell activation. Immunity 33, 326–339 (2010).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pedicord, V. A., Montalvo, W., Leiner, I. M. & Allison, J. P. Single dose of anti-CTLA-4 enhances CD8+ T-cell memory formation, function, and maintenance. Proc. Natl Acad. Sci. USA 108, 266–271 (2011).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Tietze, J. K. et al. Delineation of antigen-specific and antigen-nonspecific CD8+ memory T-cell responses after cytokine-based cancer immunotherapy. Blood 119, 3073–3083 (2012).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Braun, M. et al. IL12-mediated sensitizing of T-cell receptor-dependent and -independent tumor cell killing. Oncoimmunology 5, e1188245 (2016).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Roetman, J. J. et al. Tumor-reactive CD8+ T cells enter a TCF1+PD-1 dysfunctional state. Cancer Immunol. Res. 11, 1630–1641 (2023).

    Article 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Kroemer, G., Galassi, C., Zitvogel, L. & Galluzzi, L. Immunogenic cell stress and death. Nat. Immunol. 23, 487–500 (2022).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Leone, P. et al. MHC class I antigen processing and presenting machinery: organization, function, and defects in tumor cells. J. Natl Cancer Inst. 105, 1172–1187 (2013).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Sim, J. H. et al. IL-7RαlowCD8+ T cells from healthy individuals are anergic with defective glycolysis. J. Immunol. 205, 2968–2978 (2020).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Chikuma, S. et al. PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J. Immunol. 182, 6682–6689 (2009).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Clavijo, P. E. & Frauwirth, K. A. Anergic CD8+ T lymphocytes have impaired NF-κB activation with defects in p65 phosphorylation and acetylation. J. Immunol. 188, 1213–1221 (2012).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Zippelius, A. et al. Effector function of human tumor-specific CD8 T cells in melanoma lesions: a state of local functional tolerance. Cancer Res. 64, 2865–2873 (2004).

    Article 
    CAS 
    PubMed 

    Google Scholar
     

  • Pittet, M. J. et al. High frequencies of naive Melan-A/MART-1-specific CD8+ T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals. J. Exp. Med. 190, 705–715 (1999).

    Article 
    CAS 
    PubMed 
    PubMed Central 

    Google Scholar
     

  • Source link

    Get RawNews Daily

    Stay informed with our RawNews daily newsletter email

    This stock’s the opposite of red-hot at the moment. But I reckon it could still be one to buy

    171,885 shares of this FTSE dividend star pays an income equal to the State Pension

    John Terry makes Lionel Messi claim about Arsenal wonderkid Max Dowman

    3 passive income stocks tipped to soar 41% (or more) by 2027