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Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment

Abstract

The failure of a massive influx of tumor-infiltrating T lymphocytes to eradicate tumor cells in the tumor microenvironment is mainly due to the dysfunction of T cells hyporesponsive to tumors. T-cell exhaustion and senescence induced by malignant tumors are two important dysfunctional states that coexist in cancer patients, hindering effective antitumor immunity and immunotherapy and sustaining the suppressive tumor microenvironment. Although exhausted and senescent T cells share a similar dysfunctional role in antitumor immunity, they are distinctly different in terms of generation, development, and metabolic and molecular regulation during tumor progression. Here, we discuss the unique phenotypic and functional characteristics of these two types of dysfunctional T cells and their roles in tumor development and progression. In addition, we further discuss the potential molecular and metabolic signaling pathways responsible for the control of T-cell exhaustion and senescence in the suppressive tumor microenvironment. Understanding these critical and fundamental features should facilitate rethinking the unresponsiveness to current immunotherapies in clinical patients and lead to further development of novel and effective strategies that target different types of dysfunctional T cells to enhance cancer immunotherapy.

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Fig. 1: PD-1 and CTLA4 signaling pathways and metabolic regulations involved in T-cell exhaustion in the tumor microenvironment.
Fig. 2: Molecular pathways involved in T-cell senescence in the tumor microenvironment.

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References

  1. Zou, W. Immunosuppressive networks in the tumour environment and their therapeutic relevance. Nat. Rev. Cancer 5, 263–274 (2005).

    Article  CAS  PubMed  Google Scholar 

  2. Whiteside, T. L. The tumor microenvironment and its role in promoting tumor growth. Oncogene 27, 5904–5912 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Rosenberg, S. A. et al. Tumor progression can occur despite the induction of very high levels of self/tumor antigen-specific CD8+ T cells in patients with melanoma. J. Immunol. 175, 6169–6176 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Harlin, H., Kuna, T. V., Peterson, A. C., Meng, Y. & Gajewski, T. F. Tumor progression despite massive influx of activated CD8(+) T cells in a patient with malignant melanoma ascites. Cancer Immunol. Immunother. 55, 1185–1197 (2006).

    Article  CAS  PubMed  Google Scholar 

  5. Li, K. K. & Adams, D. H. Antitumor CD8+ T cells in hepatocellular carcinoma: present but exhausted. Hepatology 59, 1232–1234 (2014).

    Article  CAS  PubMed  Google Scholar 

  6. Ahmadzadeh, M. et al. Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 114, 1537–1544 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Baitsch, L., Fuertes-Marraco, S. A., Legat, A., Meyer, C. & Speiser, D. E. The three main stumbling blocks for anticancer T cells. Trends Immunol. 33, 364–372 (2012).

    Article  CAS  PubMed  Google Scholar 

  8. Wherry, E. J. T cell exhaustion. Nat. Immunol. 12, 492–499 (2011).

    Article  CAS  PubMed  Google Scholar 

  9. Chou, J. P. & Effros, R. B. T cell replicative senescence in human aging. Curr. Pharm. Des. 19, 1680–1698 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  10. Schietinger, A. & Greenberg, P. D. Tolerance and exhaustion: defining mechanisms of T cell dysfunction. Trends Immunol. 35, 51–60 (2014).

    Article  CAS  PubMed  Google Scholar 

  11. Reiser, J. & Banerjee, A. Effector, memory, and dysfunctional CD8(+) T cell fates in the antitumor immune response. J. Immunol. Res. 2016, 8941260 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  12. Akbar, A. N. & Henson, S. M. Are senescence and exhaustion intertwined or unrelated processes that compromise immunity? Nat. Rev. Immunol. 11, 289–295 (2011).

    Article  CAS  PubMed  Google Scholar 

  13. 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  CAS  Google Scholar 

  14. Ye, J. et al. Human regulatory T cells induce T-lymphocyte senescence. Blood 120, 2021–2031 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Ye, J. et al. Tumor-derived gammadelta regulatory T cells suppress innate and adaptive immunity through the induction of immunosenescence. J. Immunol. 190, 2403–2414 (2013).

    Article  CAS  PubMed  Google Scholar 

  16. 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 

  17. Blackburn, S. D. et al. Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 10, 29–37 (2009).

    Article  CAS  PubMed  Google Scholar 

  18. Baitsch, L. et al. Exhaustion of tumor-specific CD8(+) T cells in metastases from melanoma patients. J. Clin. Invest. 121, 2350–2360 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Zhou, Q. et al. Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 117, 4501–4510 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Jiang, Y., Li, Y. & Zhu, B. T-cell exhaustion in the tumor microenvironment. Cell Death Dis. 6, e1792 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Topalian, S. L., Drake, C. G. & Pardoll, D. M. Immune checkpoint blockade: a common denominator approach to cancer therapy. Cancer Cell 27, 450–461 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Sharma, P. & Allison, J. P. Immune checkpoint targeting in cancer therapy: toward combination strategies with curative potential. Cell 161, 205–214 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Pardoll, D. M. The blockade of immune checkpoints in cancer immunotherapy. Nat. Rev. Cancer 12, 252–264 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hayflick, L. The limited in vitro lifetime of human diploid cell strains. Exp. Cell Res. 37, 614–636 (1965).

    Article  CAS  PubMed  Google Scholar 

  26. Meloni, F. et al. Foxp3 expressing CD4+ CD25+ and CD8+CD28− T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma. Hum. Immunol. 67, 1–12 (2006).

    Article  CAS  PubMed  Google Scholar 

  27. Tsukishiro, T., Donnenberg, A. D. & Whiteside, T. L. Rapid turnover of the CD8(+)CD28(-) T-cell subset of effector cells in the circulation of patients with head and neck cancer. Cancer Immunol. Immunother. 52, 599–607 (2003).

    Article  PubMed  Google Scholar 

  28. Chen, W. H. et al. Vaccination in the elderly: an immunological perspective. Trends Immunol. 30, 351–359 (2009).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Appay, V. et al. HIV-specific CD8(+) T cells produce antiviral cytokines but are impaired in cytolytic function. J. Exp. Med. 192, 63–75 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Montes, C. L. et al. Tumor-induced senescent T cells with suppressor function: a potential form of tumor immune evasion. Cancer Res. 68, 870–879 (2008).

    Article  CAS  PubMed  Google Scholar 

  31. Wolfram, R. M. et al. Defective antigen presentation resulting from impaired expression of costimulatory molecules in breast cancer. Int. J. Cancer 88, 239–244 (2000).

    Article  CAS  PubMed  Google Scholar 

  32. Ye, J. & Peng, G. Controlling T cell senescence in the tumor microenvironment for tumor immunotherapy. Oncoimmunology 4, e994398 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  33. Ye, J. et al. TLR8 signaling enhances tumor immunity by preventing tumor-induced T-cell senescence. EMBO Mol. Med. 6, 1294–1311 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Tu, W. & Rao, S. Mechanisms underlying T cell immunosenescence: aging and cytomegalovirus infection. Front Microbiol. 7, 2111 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  35. Kamphorst, A. O. et al. Rescue of exhausted CD8 T cells by PD-1-targeted therapies is CD28-dependent. Science 355, 1423–1427 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Hui, E. et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science 355, 1428–1433 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. 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 

  38. Wherry, E. J. & Kurachi, M. Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 15, 486–499 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. & Coukos, G. Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 73, 3591–3603 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Sakuishi, K. et al. Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 207, 2187–2194 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Matsuzaki, J. et al. Tumor-infiltrating NY-ESO-1-specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. Proc. Natl Acad. Sci. USA 107, 7875–7880 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Fourcade, J. et al. CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res. 72, 887–896 (2012).

    Article  CAS  PubMed  Google Scholar 

  43. Chauvin, J. M. et al. TIGIT and PD-1 impair tumor antigen-specific CD8(+) T cells in melanoma patients. J. Clin. Invest. 125, 2046–2058 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  44. Canale, F. P. et al. CD39 expression defines cell exhaustion in tumor-infiltrating CD8(+) T cells. Cancer Res. 78, 115–128 (2018).

    Article  CAS  PubMed  Google Scholar 

  45. Williams, J. B. et al. The EGR2 targets LAG-3 and 4-1BB describe and regulate dysfunctional antigen-specific CD8+ T cells in the tumor microenvironment. J. Exp. Med. 214, 381–400 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Menk, A. V. et al. 4-1BB costimulation induces T cell mitochondrial function and biogenesis enabling cancer immunotherapeutic responses. J. Exp. Med. 215, 1091–1100 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Sheppard, K. A. et al. PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 574, 37–41 (2004).

    Article  CAS  PubMed  Google Scholar 

  48. Pereira, R. M., Hogan, P. G., Rao, A. & Martinez, G. J. Transcriptional and epigenetic regulation of T cell hyporesponsiveness. J. Leukoc. Biol. 102, 601–615 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. 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 

  50. 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 

  51. 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 

  52. Singer, M. et al. A distinct gene module for dysfunction uncoupled from activation in tumor-infiltrating T cells. Cell 166, 1500–1511 (2016).e9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Xia, A. L. et al. Genomic and epigenomic perspectives of T-cell exhaustion in cancer. Brief Funct. Genomics 18, 1113–118 (2018).

    Article  CAS  Google Scholar 

  54. Paley, M. A. et al. Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection. Science 338, 1220–1225 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Pauken, K. E. & Wherry, E. J. Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 36, 265–276 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Ghoneim, H. E. et al. De novo epigenetic programs inhibit PD-1 blockade-mediated T cell rejuvenation. Cell 170, 142–157 (2017).e19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Sen, D. R. et al. The epigenetic landscape of T cell exhaustion. Science 354, 1165–1169 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Im, S. J. et al. Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature 537, 417–421 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. 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 

  60. Weng, N. P., Akbar, A. N. & Goronzy, J. CD28(−) T cells: their role in the age-associated decline of immune function. Trends Immunol. 30, 306–312 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Campisi, J., d’Adda & di Fagagna, F. Cellular senescence: when bad things happen to good cells. Nat. Rev. Mol. Cell Biol. 8, 729–740 (2007).

    Article  CAS  PubMed  Google Scholar 

  62. Li, L. et al. TLR8-mediated metabolic control of human treg function: a mechanistic target for cancer immunotherapy. Cell Metab. 29, 103–123 (2019). e5.

    Article  CAS  PubMed  Google Scholar 

  63. Dimri, G. P. et al. A biomarker that identifies senescent human cells in culture and in aging skin in vivo. Proc. Natl Acad. Sci. USA 92, 9363–9367 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. 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 

  65. Li, H. et al. Tim-3/galectin-9 signaling pathway mediates T-cell dysfunction and predicts poor prognosis in patients with hepatitis B virus-associated hepatocellular carcinoma. Hepatology 56, 1342–1351 (2012).

    Article  CAS  PubMed  Google Scholar 

  66. Brenchley, J. M. et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8(+) T cells. Blood 101, 2711–2720 (2003).

    Article  CAS  PubMed  Google Scholar 

  67. Heffner, M. & Fearon, D. T. Loss of T cell receptor-induced Bmi-1 in the KLRG1(+) senescent CD8(+) T lymphocyte. Proc. Natl Acad. Sci. USA 104, 13414–13419 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Fourcade, J. et al. Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8(+) T cell dysfunction in melanoma patients. J. Exp. Med. 207, 2175–2186 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Huang, X. et al. Lymphoma endothelium preferentially expresses Tim-3 and facilitates the progression of lymphoma by mediating immune evasion. J. Exp. Med. 207, 505–520 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Coppe, J. P., Desprez, P. Y., Krtolica, A. & Campisi, J. The senescence-associated secretory phenotype: the dark side of tumor suppression. Annu. Rev. Pathol. 5, 99–118 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Yang, O. O. et al. Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes. Virology 332, 16–19 (2005).

    Article  CAS  PubMed  Google Scholar 

  72. Lanna, A., Henson, S. M., Escors, D. & Akbar, A. N. The kinase p38 activated by the metabolic regulator AMPK and scaffold TAB1 drives the senescence of human T cells. Nat. Immunol. 15, 965–972 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Childs, B. G. et al. Senescent cells: an emerging target for diseases of ageing. Nat. Rev. Drug Disco. 16, 718–735 (2017).

    Article  CAS  Google Scholar 

  74. Rodier, F. et al. DNA-SCARS: distinct nuclear structures that sustain damage-induced senescence growth arrest and inflammatory cytokine secretion. J. Cell Sci. 124, 68–81 (2011).

    Article  CAS  PubMed  Google Scholar 

  75. Yang, Z. Z. et al. IL-12 upregulates TIM-3 expression and induces T cell exhaustion in patients with follicular B cell non-Hodgkin lymphoma. J. Clin. Invest. 122, 1271–1282 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. 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 

  77. Muenst, S. et al. The presence of programmed death 1 (PD-1)-positive tumor-infiltrating lymphocytes is associated with poor prognosis in human breast cancer. Breast Cancer Res. Treat. 139, 667–676 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Japp, A. S. et al. Dysfunction of PSA-specific CD8+ T cells in prostate cancer patients correlates with CD38 and Tim-3 expression. Cancer Immunol. Immunother. 64, 1487–1494 (2015).

    Article  CAS  PubMed  Google Scholar 

  79. Zheng, C. et al. Landscape of infiltrating T cells in liver cancer revealed by single-cell sequencing. Cell 169, 1342–1356 (2017).e16.

    Article  CAS  PubMed  Google Scholar 

  80. Thommen, D. S. et al. Progression of lung cancer is associated with increased dysfunction of T cells defined by coexpression of multiple inhibitory receptors. Cancer Immunol. Res. 3, 1344–1355 (2015).

    Article  CAS  PubMed  Google Scholar 

  81. Chen, J., Wu, X.-J. & Wang, G.-Q. Hepatoma cells up-regulate expression of programmed cell death-1 on T cells. World J. Gastroenterol. 14, 6853 (2008).

  82. Ozkazanc, D., Yoyen-Ermis, D., Tavukcuoglu, E., Buyukasik, Y. & Esendagli, G. Functional exhaustion of CD4(+) T cells induced by co-stimulatory signals from myeloid leukaemia cells. Immunology 149, 460–471 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Ye, S. W. et al. Ex-vivo analysis of CD8+ T cells infiltrating colorectal tumors identifies a major effector-memory subset with low perforin content. J. Clin. Immunol. 26, 447–456 (2006).

    Article  PubMed  Google Scholar 

  84. Chang, W. C. et al. Clinical significance of regulatory T cells and CD8+ effector populations in patients with human endometrial carcinoma. Cancer 116, 5777–5788 (2010).

    Article  CAS  PubMed  Google Scholar 

  85. Webb, J. R. et al. Profound elevation of CD8+ T cells expressing the intraepithelial lymphocyte marker CD103 (alphaE/beta7 Integrin) in high-grade serous ovarian cancer. Gynecol. Oncol. 118, 228–236 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Urbaniak-Kujda, D. et al. Increased percentage of CD8+CD28- suppressor lymphocytes in peripheral blood and skin infiltrates correlates with advanced disease in patients with cutaneous T-cell lymphomas. Postepy Hig. Med. Dosw. 63, 355–359 (2009).

    Google Scholar 

  87. Gruber, I. V. et al. Down-regulation of CD28, TCR-zeta (zeta) and up-regulation of FAS in peripheral cytotoxic T-cells of primary breast cancer patients. Anticancer Res. 28, 779–784 (2008).

    CAS  PubMed  Google Scholar 

  88. Sledge, G. W. Advances in HER2-positive breast cancer. Clin. Adv. Hematol. Oncol. 6, 98–100 (2008).

    PubMed  Google Scholar 

  89. Filaci, G. et al. CD8+ CD28− T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers. J. Immunol. 179, 4323–4334 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Kuilman, T. et al. Oncogene-induced senescence relayed by an interleukin-dependent inflammatory network. Cell 133, 1019–1031 (2008).

    Article  CAS  PubMed  Google Scholar 

  91. Acosta, J. C. et al. Chemokine signaling via the CXCR2 receptor reinforces senescence. Cell 133, 1006–1018 (2008).

    Article  CAS  PubMed  Google Scholar 

  92. Wang, T. et al. Senescent carcinoma-associated fibroblasts upregulate IL8 to enhance prometastatic phenotypes. Mol. Cancer Res. 15, 3–14 (2017).

    Article  CAS  PubMed  Google Scholar 

  93. Capell, B. C. et al. MLL1 is essential for the senescence-associated secretory phenotype. Genes Dev. 30, 321–336 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  94. Bavik, C. et al. The gene expression program of prostate fibroblast senescence modulates neoplastic epithelial cell proliferation through paracrine mechanisms. Cancer Res. 66, 794–802 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Akbar, A. N., Henson, S. M. & Lanna, A. Senescence of T lymphocytes: implications for enhancing human immunity. Trends Immunol. 37, 866–876 (2016).

    Article  CAS  PubMed  Google Scholar 

  96. Davoodzadeh Gholami, M. et al. Exhaustion of T lymphocytes in the tumor microenvironment: significance and effective mechanisms. Cell Immunol. 322, 1–14 (2017).

    Article  CAS  PubMed  Google Scholar 

  97. Boussiotis, V. A. Molecular and biochemical aspects of the PD-1 checkpoint pathway. N. Engl. J. Med. 375, 1767–1778 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Chemnitz, J. M., Parry, R. V., Nichols, K. E., June, C. H. & Riley, J. L. SHP-1 and SHP-2 associate with immunoreceptor tyrosine-based switch motif of programmed death 1 upon primary human T cell stimulation, but only receptor ligation prevents T cell activation. J. Immunol. 173, 945–954 (2004).

    Article  CAS  PubMed  Google Scholar 

  99. Bardhan, K., Anagnostou, T. & Boussiotis, V. A. The PD1:PD-L1/2 pathway from discovery to clinical implementation. Front. Immunol. 7, 550 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  100. Quigley, M. et al. Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 16, 1147–1151 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Parry, R. V. et al. CTLA-4 and PD-1 receptors inhibit T-cell activation by distinct mechanisms. Mol. Cell Biol. 25, 9543–9553 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Schildberg, F. A., Klein, S. R., Freeman, G. J. & Sharpe, A. H. Coinhibitory pathways in the B7-CD28 ligand-receptor family. Immunity 44, 955–972 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Kwong, J. et al. p38alpha and p38gamma mediate oncogenic ras-induced senescence through differential mechanisms. J. Biol. Chem. 284, 11237–11246 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, W. et al. Sequential activation of the MEK-extracellular signal-regulated kinase and MKK3/6-p38 mitogen-activated protein kinase pathways mediates oncogenic ras-induced premature senescence. Mol. Cell Biol. 22, 3389–3403 (2002).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  105. Freund, A., Patil, C. K. & Campisi, J. p38MAPK is a novel DNA damage response-independent regulator of the senescence-associated secretory phenotype. EMBO J. 30, 1536–1548 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Lanna, A. et al. A sestrin-dependent Erk-Jnk-p38 MAPK activation complex inhibits immunity during aging. Nat. Immunol. 18, 354–363 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Chang, C. H. et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162, 1229–1241 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Cascone, T. et al. Increased tumor glycolysis characterizes immune resistance to adoptive T cell therapy. Cell Metab. 27, 977–987 (2018). e4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. McKinney, E. F. & Smith, K. G. C. Metabolic exhaustion in infection, cancer and autoimmunity. Nat. Immunol. 19, 213–221 (2018).

    Article  CAS  PubMed  Google Scholar 

  110. Ma, X. et al. Cholesterol induces CD8(+) T cell exhaustion in the tumor microenvironment. Cell Metab. 30, 143–156 (2019). e5.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  111. Bengsch, B. et al. Bioenergetic insufficiencies due to metabolic alterations regulated by the inhibitory receptor PD-1 are an early driver of CD8(+) T cell exhaustion. Immunity 45, 358–373 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. Patsoukis, N. et al. PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 6, 6692 (2015).

    Article  CAS  PubMed  Google Scholar 

  113. Ogando, J. et al. PD-1 signaling affects cristae morphology and leads to mitochondrial dysfunction in human CD8(+) T lymphocytes. J. Immunother. Cancer 7, 151 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  114. Zhang, L. & Romero, P. Metabolic control of CD8(+) T cell fate decisions and antitumor immunity. Trends Mol. Med. 24, 30–48 (2018).

    Article  CAS  PubMed  Google Scholar 

  115. Scharping, N. E. et al. The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 45, 374–388 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Gordan, J. D., Thompson, C. B. & Simon, M. C. HIF and c-Myc: sibling rivals for control of cancer cell metabolism and proliferation. Cancer Cell 12, 108–113 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Sitkovsky, M. V., Kjaergaard, J., Lukashev, D. & Ohta, A. Hypoxia-adenosinergic immunosuppression: tumor protection by T regulatory cells and cancerous tissue hypoxia. Clin. Cancer Res. 14, 5947–5952 (2008).

    Article  CAS  PubMed  Google Scholar 

  118. Croci, D. O. et al. Dynamic cross-talk between tumor and immune cells in orchestrating the immunosuppressive network at the tumor microenvironment. Cancer Immunol. Immunother. 56, 1687–1700 (2007).

    Article  PubMed  Google Scholar 

  119. Sitkovsky, M. & Lukashev, D. Regulation of immune cells by local-tissue oxygen tension: HIF1 alpha and adenosine receptors. Nat. Rev. Immunol. 5, 712–721 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Keshari, K. R. et al. Metabolic reprogramming and validation of hyperpolarized 13C lactate as a prostate cancer biomarker using a human prostate tissue slice culture bioreactor. Prostate 73, 1171–1181 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Rodrigues, T. B. et al. Magnetic resonance imaging of tumor glycolysis using hyperpolarized 13C-labeled glucose. Nat. Med. 20, 93–97 (2014).

    Article  CAS  PubMed  Google Scholar 

  122. Vegran, F., Boidot, R., Michiels, C., Sonveaux, P. & Feron, O. Lactate influx through the endothelial cell monocarboxylate transporter MCT1 supports an NF-kappaB/IL-8 pathway that drives tumor angiogenesis. Cancer Res. 71, 2550–2560 (2011).

    Article  CAS  PubMed  Google Scholar 

  123. Brand, A. et al. LDHA-associated lactic acid production blunts tumor immunosurveillance by T and NK cells. Cell Metab. 24, 657–671 (2016).

    Article  CAS  PubMed  Google Scholar 

  124. Ho, P. C. et al. Phosphoenolpyruvate is a metabolic checkpoint of anti-tumor T cell responses. Cell 162, 1217–1228 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Zhao, E. et al. Cancer mediates effector T cell dysfunction by targeting microRNAs and EZH2 via glycolysis restriction. Nat. Immunol. 17, 95–103 (2016).

    Article  CAS  PubMed  Google Scholar 

  126. Henson, S. M. et al. p38 signaling inhibits mTORC1-independent autophagy in senescent human CD8(+) T cells. J. Clin. Invest. 124, 4004–4016 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Vang, T. et al. Activation of the COOH-terminal Src kinase (Csk) by cAMP-dependent protein kinase inhibits signaling through the T cell receptor. J. Exp. Med. 193, 497–507 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Van Nguyen, T., Puebla-Osorio, N., Pang, H., Dujka, M. E. & Zhu, C. DNA damage-induced cellular senescence is sufficient to suppress tumorigenesis: a mouse model. J. Exp. Med. 204, 1453–1461 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Rodier, F. et al. Persistent DNA damage signalling triggers senescence-associated inflammatory cytokine secretion. Nat. Cell Biol. 11, 973–979 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  131. Zou, W., Wolchok, J. D. & Chen, L. PD-L1 (B7-H1) and PD-1 pathway blockade for cancer therapy: mechanisms, response biomarkers, and combinations. Sci. Transl. Med. 8, 328rv4 (2016).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  132. Pearce, E. L. Metabolism in T cell activation and differentiation. Curr. Opin. Immunol. 22, 314–320 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Zeng, H. & Chi, H. Metabolic control of regulatory T cell development and function. Trends Immunol. 36, 3–12 (2015).

    Article  CAS  PubMed  Google Scholar 

  134. MacIver, N. J., Michalek, R. D. & Rathmell, J. C. Metabolic regulation of T lymphocytes. Annu Rev. Immunol. 31, 259–283 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Gupta, P. K. et al. CD39 expression identifies terminally exhausted CD8+ T cells. PLoS Pathog. 11, e1005177 (2015).

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  136. Brenchley, J. M. et al. Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells. Blood 101, 2711–2720 (2003).

    Article  CAS  PubMed  Google Scholar 

  137. Narita, M. et al. Rb-mediated heterochromatin formation and silencing of E2F target genes during cellular senescence. Cell 113, 703–716 (2003).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

Because of space limitations, we apologize to anyone whose excellent studies have been inadvertently omitted. This work was partially funded by grants from the American Cancer Society (RSG-10-160-01-LIB, to G.P.), Melanoma Research Alliance (to G.P.), and NIH (AI097852, AI094478, and CA184379 to G.P.).

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Correspondence to Guangyong Peng.

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Zhao, Y., Shao, Q. & Peng, G. Exhaustion and senescence: two crucial dysfunctional states of T cells in the tumor microenvironment. Cell Mol Immunol 17, 27–35 (2020). https://doi.org/10.1038/s41423-019-0344-8

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