Effector, Memory, and Dysfunctional CD8+ T Cell Fates in the Antitumor Immune Response

Journal of Immunology Research

Volumn 2016, Issue , 2016, Pages

  Reiser, John ^a   Banerjee, Arnob ^a  

^a UNIVERSITY OF MARYLAND SCHOOL OF MEDICINE   (United States)

Author keywords

[No Author keywords available]

Indexed keywords

ADAPTIVE IMMUNITY; CD8+ T LYMPHOCYTE; CELL AGING; CELL FATE; EFFECTOR CELL; HUMAN; IMMUNOLOGICAL TOLERANCE; IMMUNOREGULATION; MEMORY T LYMPHOCYTE; NONHUMAN; REGULATORY T LYMPHOCYTE; REVIEW; T LYMPHOCYTE SUBPOPULATION; TRANSCRIPTION REGULATION; TUMOR IMMUNITY; TUMOR MICROENVIRONMENT; ANIMAL; CYTOLOGY; CYTOTOXICITY; GENE EXPRESSION REGULATION; GENETICS; IMMUNE SYSTEM; IMMUNOLOGICAL MEMORY; IMMUNOLOGY; IMMUNOMODULATION; LYMPHOCYTE ACTIVATION; METABOLISM; NEOPLASM; PATHOLOGY; SIGNAL TRANSDUCTION; TUMOR ASSOCIATED LEUKOCYTE;

TUMOR ANTIGEN;

ANIMALS; ANTIGENS, NEOPLASM; CD8-POSITIVE T-LYMPHOCYTES; CYTOTOXICITY, IMMUNOLOGIC; GENE EXPRESSION REGULATION, NEOPLASTIC; HUMANS; IMMUNE SYSTEM; IMMUNOLOGIC MEMORY; IMMUNOMODULATION; LYMPHOCYTE ACTIVATION; LYMPHOCYTES, TUMOR-INFILTRATING; NEOPLASMS; SIGNAL TRANSDUCTION; T-LYMPHOCYTE SUBSETS; TUMOR MICROENVIRONMENT;

EID: 84975154579     PISSN: 23148861     EISSN: 23147156     Source Type: Journal    
DOI: 10.1155/2016/8941260     Document Type: Review

References (160)

1. G. W. Fortner and M. L. Kripke, "In vitro reactivity of splenic lymphocytes from normal and UV irradiated mice against syngeneicUVinduced tumors, "TheJournal of Immunology, vol. 118, no. 4, pp. 1483-1487, 1977.
2. S. A. Rosenberg, P. Spiess, and R. Lafreniere, "Anewapproachto the adoptive immunotherapy of cancer with tumor-infiltrating lymphocytes, " Science, vol. 233, no. 4770, pp. 1318-1321, 1986.
3. S. A. Rosenberg, B. S. Packard, P. M. Aebersold et al., "Use of tumor-infiltrating lymphocyts and interleukin-2 in the immunotherapy of patients with metastatic melanoma. A preliminary report, "The New England Journal of Medicine, vol. 319, no. 25, pp. 1676-1680, 1988.
4. A.-M. Engel, I. M. Svane, S. Mouritsen, J. Rygaard, J. Clausen, and O. Werdelin, "Methylcholanthrene-induced sarcomas in nude mice have short induction times and relatively low levels of surface MHC class I expression, " APMIS, vol. 104, no. 9, pp. 629-639, 1996.
5. A.-M. Engel, I. M. Svane, J. Rygaard, and O. Werdelin, "MCA sarcomas induced in scid mice are more immunogenic than MCA sarcomas induced in congenic, immunocompetent mice, " Scandinavian Journal of Immunology, vol. 45, no. 5, pp. 463-470, 1997.
6. V. Shankaran, H. Ikeda, A. T. Bruce et al., "IFN and lymphocytes prevent primary tumour development and shape tumour immunogenicity, " Nature, vol. 410, no. 6832, pp. 1107-1111, 2001.
7. M. E. Dudley, J. R. Wunderlich, P. F. Robbins et al., "Cancer regression and autoimmunity in patients after clonal repopulation with antitumor lymphocytes, " Science, vol. 298, no. 5594, pp. 850-854, 2002.
8. F. Djenidi, J. Adam, A. Goubar et al., "CD8+CD103+ tumorinfiltrating lymphocytes are tumor-specific tissue-resident memory T cells and a prognostic factor for survival in lung cancer patients, " Journal of Immunology, vol. 194, no. 7, pp. 3475-3486, 2015.
9. M. E. Dudley, J. C. Yang, R. Sherry et al., "Adoptive cell therapy for patients with metastatic melanoma: evaluation of intensive myeloablative chemoradiation preparative regimens, " Journal of Clinical Oncology, vol. 26, no. 32, pp. 5233-5239, 2008.
10. J. Galon, A. Costes, F. Sanchez-Cabo et al., "Type, density, and location of immune cells within human colorectal tumors predict clinical outcome, " Science, vol. 313, no. 5795, pp. 1960-1964, 2006.
11. J. Kmiecik, A. Poli, N. H. C. Brons et al., "Elevated CD3+ and CD8+ tumor-infiltrating immune cells correlate with prolonged survival in glioblastoma patients despite integrated immunosuppressive mechanisms in the tumor microenvironment and at the systemic level, " Journal of Neuroimmunology, vol. 264, no. 1-2, pp. 71-83, 2013.
12. S. M. A. Mahmoud, E. C. Paish, D. G. Powe et al., "Tumorinfiltrating CD8+ lymphocytes predict clinical outcome in breast cancer, " Journal of Clinical Oncology, vol. 29, no. 15, pp. 1949-1955, 2011.
13. M. Wang, B. Yin, H. Y. Wang, and R.-F. Wang, "Current advances in T-cell-based cancer immunotherapy, " Immunotherapy, vol. 6, no. 12, pp. 1265-1278, 2014.
14. K. M. Kaluza, J. M. Thompson, T. J. Kottke, H. C. Flynn Gilmer, D. L. Knutson, and R. G. Vile, "Adoptive T cell therapy promotes the emergence of genomically altered tumor escape variants, " International Journal ofCancer, vol. 131, no. 4, pp. 844-854, 2012.
15. T. Straetemans, C. Berrevoets, M. Coccoris et al., "Recurrence of melanoma following T cell treatment: continued antigen expression in a tumor that evades T cell recruitment, "Molecular Therapy, vol. 23, no. 2, pp. 396-406, 2015.
16. L. Baitsch, P. Baumgaertner, E. Devêvre et al., "Exhaustion of tumor-specific CD8+ T cells in metastases from melanoma patients, " Journal of Clinical Investigation, vol. 121, no. 6, pp. 2350-2360, 2011.
17. J. Fourcade, Z. Sun, M. Benallaoua et al., "Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients, " The Journal of Experimental Medicine, vol. 207, no. 10, pp. 2175-2186, 2010.
18. F. Broere, S. G. Apasov, M. V. Sitkovsky, and W. van Eden, "A2 T cell subsets and T cell-mediated immunity, " in Principles of Immunopharmacology, pp. 15-27, Birkhäuser, Basel, Switzerland, 2011.
19. S. Sarkar, V. Kalia, W. N. Haining, B. T. Konieczny, S. Subramaniam, and R. Ahmed, "Functional and genomic profiling of effector CD8 T cell subsets with distinct memory fates, " Journal of Experimental Medicine, vol. 205, no. 3, pp. 625-640, 2008.
20. M. Shipkova and E. Wieland, "Surface markers of lymphocyte activation and markers of cell proliferation, " Clinica Chimica Acta, vol. 413, no. 17-18, pp. 1338-1349, 2012.
21. V. Kalia, S. Sarkar, S. Subramaniam, W. N. Haining, K. A. Smith, and R. Ahmed, "Prolonged interleukin-2R expression on virus-specific CD8+ T cells favors terminal-effector differentiation in vivo, " Immunity, vol. 32, no. 1, pp. 91-103, 2010.
22. M. E. Pipkin, J. A. Sacks, F. Cruz-Guilloty, M. G. Lichtenheld, M. J. Bevan, and A. Rao, "Interleukin-2 and inflammation induce distinct transcriptional programs that promote the differentiation of effector cytolytic T cells, " Immunity, vol. 32, no. 1, pp. 79-90, 2010.
23. M. L. Arbonés, D. C. Ord, K. Ley et al., "Lymphocyte homing and leukocyte rolling and migration are impaired in L-selectindeficient mice, " Immunity, vol. 1, no. 4, pp. 247-260, 1994.
24. R. Förster, A. Schubel, D. Breitfeld et al., "CCR7 coordinates the primary immune response by establishing functional microenvironments in secondary lymphoid organs, " Cell, vol. 99, no. 1, pp. 23-33, 1999.
25. F. Sallusto, D. Lenig, R. Förster, M. Lipp, and A. Lanzavecchia, "Two subsets of memory T lymphocytes with distinct homing potentials and effector functions, " Nature, vol. 401, no. 6754, pp. 708-712, 1999.
26. M. F. Bachmann, P. Wolint, K. Schwarz, P. Jäger, and A. Oxenius, "Functional properties and lineage relationship of CD8+ T cell subsets identified by expression of IL-7 receptor and CD62L, " The Journal of Immunology, vol. 175, no. 7, pp. 4686-4696, 2005.
27. D. Masopust, V. Vezys, A. L. Marzo, and L. Lefrançois, "Preferential localization of effector memory cells in nonlymphoid tissue, " Science, vol. 291, no. 5512, pp. 2413-2417, 2001.
28. F. Sallusto, J. Geginat, and A. Lanzavecchia, "Central memory and effector memory T cell subsets: function, generation, and maintenance, " Annual Review of Immunology, vol. 22, pp. 745-763, 2004.
29. E. J. Wherry, "T cell exhaustion, " Nature Immunology, vol. 12, no. 6, pp. 492-499, 2011.
30. S. D. Blackburn, H. Shin, W. N. Haining et al., "Coregulation of CD8+ T cell exhaustion bymultiple inhibitory receptors during chronic viral infection, " Nature Immunology, vol. 10, no. 1, pp. 29-37, 2009.
31. E. J. Wherry and M. Kurachi, "Molecular and cellular insights into T cell exhaustion, " Nature Reviews Immunology, vol. 15, no. 8, pp. 486-499, 2015.
32. L. Chen and D. B. Flies, "Molecular mechanisms of T cell costimulation and co-inhibition, " Nature Reviews Immunology, vol. 13, no. 4, pp. 227-242, 2013.
33. S. A. Fuertes Marraco, N. J. Neubert, G. Verdeil, and D. E. Speiser, "Inhibitory receptors beyond T cell exhaustion, " Frontiers in Immunology, vol. 6, article 310, 2015.
34. M. Srinivasan and K. A. Frauwirth, "Reciprocal NFAT1 and NFAT2 nuclear localization in CD8+ anergic T cells is regulated by suboptimal calcium signaling, " The Journal of Immunology, vol. 179, no. 6, pp. 3734-3741, 2007.
35. S. O'Brien, R. M. Thomas, G. B. Wertheim, F. Zhang, H. Shen, and A. D. Wells, "Ikaros imposes a barrier to CD8+ T cell differentiation by restricting autocrine IL-2 production, " Journal of Immunology, vol. 192, no. 11, pp. 5118-5129, 2014.
36. M.-S. Jeon, A. Atfield, K. Venuprasad et al., "Essential role of the E3 ubiquitin ligase Cbl-b in T cell anergy induction, " Immunity, vol. 21, no. 2, pp. 167-177, 2004.
37. J. F. Grosso, C. C. Kelleher, T. J. Harris et al., "LAG-3 regulates CD8+ T cell accumulation and effector function inmurine selfand tumor-tolerance systems, " Journal of Clinical Investigation, vol. 117, no. 11, pp. 3383-3392, 2007.
38. A. Schietinger, J. J. Delrow, R. S. Basom, J. N. Blattman, and P. D. Greenberg, "Rescued tolerant CD8 T cells are preprogrammed to reestablish the tolerant state, " Science, vol. 335, no. 6069, pp. 723-727, 2012.
39. S. Chikuma, S. Terawaki, T. Hayashi et al., "PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo, "The Journal of Immunology, vol. 182, no. 11, pp. 6682-6689, 2009.
40. S. E. Barnes, Y. Wang, L. Chen et al., "T cell-NF-B activation is required for tumor control in vivo, " Journal for Immunotherapy of Cancer, vol. 3, article 1, 2015.
41. P. Ghosh, A. Sica, H. A. Young et al., "Alterations in NFB/Rel family proteins in splenic T-cells from tumor-bearing mice and reversal following therapy, " Cancer Research, vol. 54, no. 11, pp. 2969-2972, 1994.
42. R. B. Effros, M. Dagarag, C. Spaulding, and J. Man, "The role of CD8+ T-cell replicative senescence in human aging, " Immunological Reviews, vol. 205, pp. 147-157, 2005.
43. F. Meloni, M. Morosini, N. Solari et al., "Foxp3 expressing CD4+ CD25+ and CD8+CD28 T regulatory cells in the peripheral blood of patients with lung cancer and pleural mesothelioma, " Human Immunology, vol. 67, no. 1-2, pp. 1-12, 2006.
44. J. M. Brenchley, N. J. Karandikar, M. R. Betts et al., "Expression of CD57 defines replicative senescence and antigen-induced apoptotic death of CD8+ T cells, " Blood, vol. 101, no. 7, pp. 2711-2720, 2003.
45. X.-F. Bai, J.-X. Gao, J. Liu, J. Wen, P. Zheng, and Y. Liu, "On the site andmode of antigen presentation for the initiation of clonal expansion of CD8 T cells specific for a natural tumor antigen, " Cancer Research, vol. 61, no. 18, pp. 6860-6867, 2001.
46. A. L. Marzo, R. A. Lake, D. Lo et al., "Tumor antigens are constitutively presented in the draining lymph nodes, " The Journal of Immunology, vol. 162, no. 10, pp. 5838-5845, 1999.
47. E. D. Thompson, H. L. Enriquez, Y.-X. Fu, and V. H. Engelhard, "Tumor masses support naive T cell infiltration, activation, and differentiation into effectors, " Journal of ExperimentalMedicine, vol. 207, no. 8, pp. 1791-1804, 2010.
48. M. C. Wolkers, G. Stoetter, F. A. Vyth-Dreese, and T. N. M. Schumacher, "Redundancy of direct priming and crosspriming in tumor-specific CD8+ T cell responses, " The Journal of Immunology, vol. 167, no. 7, pp. 3577-3584, 2001.
49. L. Baitsch, S. A. Fuertes-Marraco, A. Legat, C. Meyer, and D. E. Speiser, "The three main stumbling blocks for anticancer T cells, " Trends in Immunology, vol. 33, no. 7, pp. 364-372, 2012.
50. Y. Kaufmann, G. Berke, and Z. Eshhar, "Cytotoxic T lymphocyte hybridomas that mediate specific tumor-cell lysis in vitro, " Proceedings of the National Academy of Sciences of the United States of America, vol. 78, no. 4, pp. 2502-2506, 1981.
51. B. Liu, E. R. Podack, J. P. Allison, and T. R. Malek, "Generation of primary tumor-specific CTL in vitro to immunogenic and poorly immunogenic mouse tumors, " The Journal of Immunology, vol. 156, no. 3, pp. 1117-1125, 1996.
52. R. Perret and F. Ronchese, "Effector CD8+ T cells activated in vitro confer immediate and long-term tumor protection in vivo, " European Journal of Immunology, vol. 38, no. 10, pp. 2886-2895, 2008.
53. D. C. Palmer, S. Balasubramaniam, K.-I. Hanada et al., "Vaccine-stimulated, adoptively transferred CD8+ T cells traffic indiscriminately and ubiquitously while mediating specific tumor destruction, "The Journal of Immunology, vol. 173, no. 12, pp. 7209-7216, 2004.
54. C. Yee, J. A. Thompson, D. Byrd et al., "Adoptive T cell therapy using antigen-specific CD8+ T cell clones for the treatment of patients with metastatic melanoma: In vivo persistence, migration, and antitumor effect of transferred T cells, " Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 25, pp. 16168-16173, 2002.
55. M. A. Williams and M. J. Bevan, "Effector and memory CTL differentiation, " Annual Review of Immunology, vol. 25, pp. 171-192, 2007.
56. C. A. Klebanoff, L. Gattinoni, and N. P. Restifo, "CD8+ Tcell memory in tumor immunology and immunotherapy, " Immunological Reviews, vol. 211, pp. 214-224, 2006.
57. D. Masopust and L. J. Picker, "Hidden memories: frontline memory T cells and early pathogen interception, " The Journal of Immunology, vol. 188, no. 12, pp. 5811-5817, 2012.
58. S. M. Kaech, S. Hemby, E. Kersh, and R. Ahmed, "Molecular and functional profiling ofmemory CD8 T cell differentiation, " Cell, vol. 111, no. 6, pp. 837-851, 2002.
59. K. Murali-Krishna, J. D. Altman, M. Suresh et al., "Counting antigen-specific CD8 T cells: A reevaluation of bystander activation during viral infection, " Immunity, vol. 8, no. 2, pp. 177-187, 1998.
60. E. J. Wherry and R. Ahmed, "Memory CD8 T-cell differentiation during viral infection, " Journal of Virology, vol. 78, no. 11, pp. 5535-5545, 2004.
61. P. Beckhove, M. Feuerer, M. Dolenc et al., "Specifically activated memory T cell subsets fromcancer patients recognize and reject xenotransplanted autologous tumors, " The Journal of Clinical Investigation, vol. 114, no. 1, pp. 67-76, 2004.
62. C. Egelston, D. Simons, A. Miyahira, and P. Lee, "Effector and memory CD8 T cells and central memory CD4 T cell dominate a proliferation deficient T cell population in the primary tumor of breast cancer patients, " The Journal of Immunology, vol. 190, 2013.
63. M. Feuerer, M. Rocha, L. Bai et al., "Enrichment of memory T cells and other profound immunological changes in the bone marrow from untreated breast cancer patients, " International Journal of Cancer, vol. 92, no. 1, pp. 96-105, 2001.
64. F. Pagès, A. Berger, M. Camus et al., "Effector memory T cells, early metastasis, and survival in colorectal cancer, " The New England Journal of Medicine, vol. 353, no. 25, pp. 2654-2666, 2005.
65. A. G. Chapuis, J. A. Thompson, K. A. Margolin et al., "Transferred melanoma-specific CD8+ T cells persist, mediate tumor regression, and acquire central memory phenotype, " Proceedings of the National Academy of Sciences of the United States of America, vol. 109, no. 12, pp. 4592-4597, 2012.
66. L.-X. Wang, J. Kjaergaard, P. A. Cohen, S. Shu, and G. E. Plautz, "Memory T cells originate fromadoptively transferred effectors and reconstituting host cells after sequential lymphodepletion and adoptive immunotherapy, " The Journal of Immunology, vol. 172, no. 6, pp. 3462-3468, 2004.
67. L. Gattinoni, C. A. Klebanoff, D. C. Palmer et al., "Acquisition of full effector function in vitro paradoxically impairs the in vivo antitumor efficacy of adoptively transferred CD8+ T cells, " The Journal of Clinical Investigation, vol. 115, no. 6, pp. 1616-1626, 2005.
68. S. A. Rosenberg and M. E. Dudley, "Cancer regression in patients with metastatic melanoma after the transfer of autologous antitumor lymphocytes, " Proceedings of the National Academy of Sciences of the United States of America, vol. 101, supplement 2, pp. 14639-14645, 2004.
69. D. J. Powell Jr., M. E. Dudley, P. F. Robbins, and S. A. Rosenberg, "Transition of late-stage effector T cells to CD27+ CD28+ tumor-reactive effector memory T cells in humans after adoptive cell transfer therapy, " Blood, vol. 105, no. 1, pp. 241-250, 2005.
70. C. A. Klebanoff, L. Gattinoni, P. Torabi-Parizi et al., "Central memory self/tumor-reactive CD8+ T cells confer superior antitumor immunity compared with effector memory T cells, " Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 27, pp. 9571-9576, 2005.
71. F. Wu, W. Zhang, H. Shao et al., "Human effector T cells derived from central memory cells rather than CD8+T cells modified by tumor-specific TCR gene transfer possess superior traits for adoptive immunotherapy, " Cancer Letters, vol. 339, no. 2, pp. 195-207, 2013.
72. L. Gattinoni, E. Lugli, Y. Ji et al., "Ahumanmemory T cell subset with stem cell-like properties, " Nature Medicine, vol. 17, no. 10, pp. 1290-1297, 2011.
73. M. Papatriantafyllou, "T cell memory: the stem of T cell memory, " Nature Reviews Immunology, vol. 11, pp. 716-717, 2011.
74. J. M. Schenkel and D. Masopust, "Tissue-resident memory T cells, " Immunity, vol. 41, no. 6, pp. 886-897, 2014.
75. E. J. Wherry, J. N. Blattman, K. Murali-Krishna, R. Van Der Most, and R. Ahmed, "Viral persistence alters CD8 Tcell immunodominance and tissue distribution and results in distinct stages of functional impairment, " Journal of Virology, vol. 77, no. 8, pp. 4911-4927, 2003.
76. Y. Jiang, Y. Li, and B. Zhu, "T-cell exhaustion in the tumor microenvironment, " Cell Death & Disease, vol. 6, no. 6, Article ID e1792, 2015.
77. Y. Iwai, M. Ishida, Y. Tanaka, T. Okazaki, T. Honjo, and N. Minato, "Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PDL1 blockade, " Proceedings of the National Academy of Sciences of the United States of America, vol. 99, no. 19, pp. 12293-12297, 2002.
78. H. Dong, S. E. Strome, D. R. Salomao et al., "Tumor-associated B7-H1 promotes T-cell apoptosis: A potential mechanism of immune evasion, " Nature Medicine, vol. 8, no. 8, pp. 793-800, 2002.
79. J. Fourcade, P. Kudela, Z. Sun et al., "PD-1 is a regulator of NYESO-1-specific CD8+ T cell expansion in melanoma patients, " Journal of Immunology, vol. 182, no. 9, pp. 5240-5249, 2009.
80. A. J. Gehring, Z. Z. Ho, A. T. Tan et al., "Profile of tumor antigenspecific CD8 T cells in patients with hepatitis B virus-related hepatocellular carcinoma, " Gastroenterology, vol. 137, no. 2, pp. 682-690, 2009.
81. H. Saito, H. Kuroda, T. Matsunaga, T. Osaki, and M. Ikeguchi, "Increased PD-1 expression on CD4+ and CD8+ T cells is involved in immune evasion in gastric cancer, " Journal of Surgical Oncology, vol. 107, no. 5, pp. 517-522, 2013.
82. R. Yamamoto, M. Nishikori, T. Kitawaki et al., "PD-1 PD-1 ligand interaction contributes to immunosuppressive microenvironment of Hodgkin lymphoma, " Blood, vol. 111, no. 6, pp. 3220-3224, 2008.
83. J. G. Egen, M. S. Kuhns, and J. P. Allison, "CTLA-4: new insights into its biological function and use in tumor immunotherapy, " Nature Immunology, vol. 3, no. 7, pp. 611-618, 2002.
84. C. Fellne, "Ipilimumab (Yervoy) prolongs survival in advanced melanoma: serious side effects and a hefty price tag may limit its use, " P and T, vol. 37, no. 9, pp. 503-530, 2012.
85. J. Duraiswamy, K. M. Kaluza, G. J. Freeman, and G. Coukos, "Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors, " Cancer Research, vol. 73, no. 12, pp. 3591-3603, 2013.
86. D. L. Barber, E. J. Wherry, D. Masopust et al., "Restoring function in exhausted CD8 T cells during chronic viral infection, " Nature, vol. 439, no. 7077, pp. 682-687, 2006.
87. A. Zippelius, P. Batard, V. Rubio-Godoy et al., "Effector function of human tumor-specific CD8 T cells in melanoma lesions: A state of local functional tolerance, " Cancer Research, vol. 64, no. 8, pp. 2865-2873, 2004.
88. A. Ito, S. Kondo, K. Tada, and S. Kitano, "Clinical development of immune checkpoint inhibitors, " BioMed Research International, vol. 2015, Article ID 605478, 12 pages, 2015.
89. D. M. Pardoll, "The blockade of immune checkpoints in cancer immunotherapy, " Nature Reviews Cancer, vol. 12, no. 4, pp. 252-264, 2012.
90. P. Sharma and J. P. Allison, "The future of immune checkpoint therapy, " Science, vol. 348, no. 6230, pp. 56-61, 2015.
91. A. Legat, D. E. Speiser, H. Pircher, D. Zehn, and S. A. Fuertes Marraco, "Inhibitory receptor expression depends more dominantly on differentiation and activation than 'exhaustion' of human CD8 T cells, " Frontiers in Immunology, vol. 4, article 455, 2013.
92. A. Gros, P. F. Robbins, X. Yao et al., "PD-1 identifies the patientspecific CD8+ tumor-reactive repertoire infiltrating human tumors, "The Journal of Clinical Investigation, vol. 124, no. 5, pp. 2246-2259, 2014.
93. J. Duraiswamy, C. C. Ibegbu, D. Masopust et al., "Phenotype, function, and gene expression profiles of programmed death-1(hi) CD8 T cells in healthy human adults, " Journal of Immunology, vol. 186, no. 7, pp. 4200-4212, 2011.
94. M. Ahmadzadeh, L. A. Johnson, B. Heemskerk et al., "Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired, " Blood, vol. 114, no. 8, pp. 1537-1544, 2009.
95. F. Wei, S. Zhong, Z. Ma et al., "Strength of PD-1 signaling differentially affects T-cell effector functions, " Proceedings of the National Academy of Sciences of the United States of America, vol. 110, no. 27, pp. E2480-E2489, 2013.
96. J. P. Allison, "Immune checkpoint blockade in cancer therapy: the 2015 lasker-debakey clinical medical research award, " Journal of theAmericanMedical Association, vol. 314, no. 11, pp. 1113-1114, 2015.
97. Y. Xing and K. A. Hogquist, "T-cell tolerance: central and peripheral, " Cold Spring Harbor Perspectives in Biology, vol. 4, no. 6, 2012.
98. A. N. Houghton and J. A. Guevara-Patiño, "Immune recognition of self in immunity against cancer, "The Journal of Clinical Investigation, vol. 114, no. 4, pp. 468-471, 2004.
99. J. Crespo, H. Sun, T. H. Welling, Z. Tian, and W. Zou, "T cell anergy, exhaustion, senescence, and stemness in the tumor microenvironment, " Current Opinion in Immunology, vol. 25, no. 2, pp. 214-221, 2013.
100. C. Jochems and J. Schlom, "Tumor-infiltrating immune cells and prognosis: the potential link between conventional cancer therapy and immunity, " Experimental Biology andMedicine, vol. 236, no. 5, pp. 567-579, 2011.
101. R. Lechler, J.-G. Chai, F. Marelli-Berg, and G. Lombardi, "The contributions of T-cell anergy to peripheral T-cell tolerance, " Immunology, vol. 103, no. 3, pp. 262-269, 2001.
102. W. Zou and L. Chen, "Inhibitory B7-family molecules in the tumour microenvironment, " Nature Reviews Immunology, vol. 8, no. 6, pp. 467-477, 2008.
103. T. J. Curiel, S. Wei, H. Dong et al., "Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity, " Nature Medicine, vol. 9, no. 5, pp. 562-567, 2003.
104. I. Kryczek, L. Zou, P. Rodriguez et al., "B7-H4 expression identifies a novel suppressive macrophage population in human ovarian carcinoma, "The Journal of Experimental Medicine, vol. 203, no. 4, pp. 871-881, 2006.
105. P. S. Kim and R. Ahmed, "Features of responding T cells in cancer and chronic infection, " Current Opinion in Immunology, vol. 22, no. 2, pp. 223-230, 2010.
106. E. J. Wherry, S.-J. Ha, S. M. Kaech et al., "Molecular signature of CD8+ T cell exhaustion during chronic viral infection, " Immunity, vol. 27, no. 4, pp. 670-684, 2007.
107. K. Staveley-O'Carroll, E. Sotomayor, J. Montgomery et al., "Induction of antigen-specific T cell anergy: An early event in the course of tumor progression, " Proceedings of the National Academy of Sciences of the United States of America, vol. 95, no. 3, pp. 1178-1183, 1998.
108. G. Filaci, M. Fravega, S. Negrini et al., "Nonantigen specific CD8+ T suppressor lymphocytes originate from CD8+CD28 T cells and inhibit both T-cell proliferation and CTL function, " Human Immunology, vol. 65, no. 2, pp. 142-156, 2004.
109. O. O. Yang, H. Lin, M. Dagarag, H. L. Ng, R. B. Effros, and C. H. Uittenbogaart, "Decreased perforin and granzyme B expression in senescent HIV-1-specific cytotoxic T lymphocytes, " Virology, vol. 332, no. 1, pp. 16-19, 2005.
110. T. Tsukishiro, A. D. Donnenberg, and T. L. Whiteside, "Rapid turnover of the CD8+CD28 T-cell subset of effector cells in the circulation of patients with head and neck cancer, " Cancer Immunology, Immunotherapy, vol. 52, no. 10, pp. 599-607, 2003.
111. G. Filaci, D. Fenoglio, M. Fravega et al., "CD8+CD28 T regulatory lymphocytes inhibiting T cell proliferative and cytotoxic functions infiltrate human cancers, " Journal of Immunology, vol. 179, no. 7, pp. 4323-4334, 2007.
112. C. L. Montes, A. I. Chapoval, J. Nelson et al., "Tumor-induced senescent T cells with suppressor function: A potential form of tumor immune evasion, " Cancer Research, vol. 68, no. 3, pp. 870-879, 2008.
113. Y. Zhang, L. W. Pfannenstiel, E. Bolesta et al., "Interleukin-7 inhibits tumor-inducedCD27?CD28 suppressor T cells: implications for cancer immunotherapy, " Clinical Cancer Research, vol. 17, no. 15, pp. 4975-4986, 2011.
114. H. Pilch, H. Hoehn, M. Schmidt et al., "CD8+CD45RA+CD27-CD28-T-cell subset in PBL of cervical cancer patients representing CD8+T-cells being able to recognize cervical cancer associated antigens provided by HPV 16 E7, " Zentralblatt fur Gynakologie, vol. 124, no. 8-9, pp. 406-412, 2002.
115. O. O. Onyema, L. Decoster, R. Njemini et al., "Shifts in subsets of CD8+ T-cells as evidence of immunosenescence in patients with cancers affecting the lungs: An observational case-control study, " BMC Cancer, vol. 15, article 1016, 2015.
116. G. Dranoff, "Cytokines in cancer pathogenesis and cancer therapy, " Nature Reviews Cancer, vol. 4, no. 1, pp. 11-22, 2004.
117. G. Landskron, M. De la Fuente, P. Thuwajit, C. Thuwajit, and M. A. Hermoso, "Chronic inflammation and cytokines in the tumor microenvironment, " Journal of Immunology Research, vol. 2014, Article ID149185, 19 pages, 2014.
118. A. M. McDonnell, B. W. S. Robinson, and A. J. Currie, "Tumor antigen cross-presentation and the dendritic cell: where it all begins" Clinical and Developmental Immunology, vol. 2010, Article ID 539519, 9 pages, 2010.
119. T. L. Whiteside, "The tumor microenvironment and its role in promoting tumor growth, " Oncogene, vol. 27, no. 45, pp. 5904-5912, 2008.
120. K. A. Waugh, S. M. Leach, and J. E. Slansky, "Targeting transcriptional regulators of CD8+ T cell dysfunction to boost antitumor immunity, " Vaccines, vol. 3, no. 3, pp. 771-802, 2015.
121. S. Bandyopadhyay, N. Soto-Nieves, and F. Macián, "Transcriptional regulation of T cell tolerance, " Seminars in Immunology, vol. 19, no. 3, pp. 180-187, 2007.
122. K. E. Pauken and E. J. Wherry, "Overcoming T cell exhaustion in infection and cancer, " Trends in Immunology, vol. 36, no. 4, pp. 265-276, 2015.
123. K. J. Oestreich, H. Yoon, R. Ahmed, and J. M. Boss, "NFATc1 regulates PD-1 expression upon T cell activation, " Journal of Immunology, vol. 181, no. 7, pp. 4832-4839, 2008.
124. P. E. Clavijo andK. A. Frauwirth, "AnergicCD8+ T lymphocytes have impaired NF-B activation with defects in p65 phosphorylation and acetylation, " Journal of Immunology, vol. 188, no. 3, pp. 1213-1221, 2012.
125. N. Chaput, S. Louafi, A. Bardier et al., "Identification of CD8+CD25+Foxp3+ suppressive T cells in colorectal cancer tissue, " Gut, vol. 58, no. 4, pp. 520-529, 2009.
126. Y. Kiniwa, Y. Miyahara, H. Y. Wang et al., "CD8+ Foxp3+ regulatory T cells mediate immunosuppression in prostate cancer, " Clinical Cancer Research, vol. 13, no. 23, pp. 6947-6958, 2007.
127. C. T. Mayer, S. Floess, A. M. Baru, K. Lahl, J. Huehn, and T. Sparwasser, "CD8+Foxp3+ T cells share developmental and phenotypic features with classical CD4+Foxp3+ regulatory T cells but lack potent suppressive activity, " European Journal of Immunology, vol. 41, no. 3, pp. 716-725, 2011.
128. M. C. Ramello, J. Tosello Boari, F. P. Canale et al., "Tumorinduced senescent T cells promote the secretion of proinflammatory cytokines and angiogenic factors by human monocytes/macrophages through a mechanism that involves Tim-3 and CD40L, " Cell Death and Disease, vol. 5, no. 11, Article ID e1507, 2014.
129. G. Li, Q. Yang, Y. Zhu et al., "T-bet and eomes regulate the balance between the effector/central memory T cells versus memory stem like T cells, " PLoS ONE, vol. 8, no. 6, Article ID e67401, 2013.
130. A. M. Intlekofer, N. Takemoto, E. J. Wherry et al., "Effector and memory CD8+ T cell fate coupled by T-bet and eomesodermin, " Nature Immunology, vol. 6, pp. 1236-1244, 2005.
131. Y. Zhu, S. Ju, E. Chen et al., "T-bet and eomesodermin are required for T cell-mediated antitumor immune responses, " Journal of Immunology, vol. 185, no. 6, pp. 3174-3183, 2010.
132. M. M. Berrien-Elliott, J. Yuan, L. E. Swier et al., "Checkpoint blockade immunotherapy relies on T-bet but not Eomes to induce effector function in tumor-infiltrating CD8+ T cells, " Cancer Immunology Research, vol. 3, no. 2, pp. 116-124, 2015.
133. C. Kao, K. J. Oestreich, M. A. Paley et al., "Transcription factor T-bet represses expression of the inhibitory receptor PD-1 and sustains virus-specific CD8+ T cell responses during chronic infection, " Nature Immunology, vol. 12, no. 7, pp. 663-671, 2011.
134. C. Song, K. Sadashivaiah, A. Furusawa, E. Davila, K. Tamada, and A. Banerjee, "Eomesodermin is required for antitumor immunity mediated by 4-1BB-agonist immunotherapy, " Oncoimmunology, vol. 3, no. 2, article e27680, 2014.
135. M. A. Paley, D. C. Kroy, P. M. Odorizzi et al., "Progenitor and terminal subsets of CD8+ T cells cooperate to contain chronic viral infection, " Science, vol. 338, no. 6111, pp. 1220-1225, 2012.
136. M. Buggert, J. Tauriainen, T. Yamamoto et al., "T-bet and Eomes are differentially linked to the exhausted phenotype of CD8+ T cells in HIV infection, " PLoS Pathogens, vol. 10, no. 7, Article ID e1004251, 2014.
137. R. L. Rutishauser, G. A. Martins, S. Kalachikov et al., "Transcriptional repressor Blimp-1 promotes CD8+ T cell terminal differentiation and represses the acquisition of central memory T cell properties, " Immunity, vol. 31, no. 2, pp. 296-308, 2009.
138. P. Lu, B. A. Youngblood, J. W. Austin et al., "Blimp-1 represses CD8 T cell expression of PD-1 using a feed-forward transcriptional circuit during acute viral infection, " Journal of Experimental Medicine, vol. 211, no. 3, pp. 515-527, 2014.
139. G. J. Martinez, R. M. Pereira, T. äijö et al., "The transcription factor NFAT promotes exhaustion of activated CD8+ T cells, " Immunity, vol. 42, no. 2, pp. 265-278, 2015.
140. Y. Zheng, Y. Zha, and T. F. Gajewski, "Molecular regulation of T-cell anergy, " EMBO Reports, vol. 9, no. 1, pp. 50-55, 2008.
141. R. Lin, L. Chen, G. Chen et al., "Targeting miR-23a in CD8+ cytotoxic T lymphocytes prevents tumor-dependent immunosuppression, " The Journal of Clinical Investigation, vol. 124, no. 12, pp. 5352-5367, 2014.
142. H. Shin, S. D. Blackburn, A. M. Intlekofer et al., "A role for the transcriptional repressor blimp-1 in CD8+ T cell exhaustion during chronic viral infection, " Immunity, vol. 31, no. 2, pp. 309-320, 2009.
143. M. Kurachi, R. A. Barnitz, N. Yosef et al., "The transcription factor BATF operates as an essential differentiation checkpoint in early effector CD8+ T cells, " Nature Immunology, vol. 15, no. 4, pp. 373-383, 2014.
144. M. Quigley, F. Pereyra, B. Nilsson et al., "Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF, " Nature Medicine, vol. 16, no. 10, pp. 1147-1151, 2010.
145. M. G. di Bari, M. E. C. Lutsiak, S. Takai et al., "TGF-modulates the functionality of tumor-infiltrating CD8+ T cells through effects on TCR signaling and Spred1 expression, " Cancer Immunology, Immunotherapy, vol. 58, no. 11, pp. 1809-1818, 2009.
146. D. A. Thomas and J. Massagué, "TGF-directly targets cytotoxic T cell functions during tumor evasion of immune surveillance, " Cancer Cell, vol. 8, no. 5, pp. 369-380, 2005.
147. M.-L. Chen, M. J. Pittet, L. Gorelik et al., "Regulatory T cells suppress tumor-specific CD8 T cell cytotoxicity through TGF-signals in vivo, " Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 2, pp. 419-424, 2005.
148. T. R. Mempel, M. J. Pittet, K. Khazaie et al., "Regulatory T cells reversibly suppress cytotoxic T cell function independent of effector differentiation, " Immunity, vol. 25, no. 1, pp. 129-141, 2006.
149. M. O. Li and R. A. Flavell, "TGF-: A master of all T cell trades, " Cell, vol. 134, no. 3, pp. 392-404, 2008.
150. T. L. Stephen, M. R. Rutkowski, M. J. Allegrezza et al., "Transforming growth factor-mediated suppression of antitumor T cells requires Foxp1 transcription factor expression, " Immunity, vol. 41, no. 3, pp. 427-439, 2014.
151. A. LeFloc'h, A. Jalil, I. Vergnonet al., "E7 integrin interaction with E-cadherin promotes antitumor CTL activity by triggering lytic granule polarization and exocytosis, " The Journal of Experimental Medicine, vol. 204, no. 3, pp. 559-570, 2007.
152. M. Mokrani, J. Klibi, D. Bluteau, G. Bismuth, and F. Mami-Chouaib, "Smad and NFAT pathways cooperate to induce CD103 expression in human CD8 T lymphocytes, " Journal of Immunology, vol. 192, no. 5, pp. 2471-2479, 2014.
153. S. Schwartzkopff, S. Woyciechowski, U. Aichele et al., "TGF-downregulatesKLRG1 expression inmouse and humanCD8+ T cells, " European Journal of Immunology, vol. 45, no. 8, pp. 2212-2217, 2015.
154. J. G. Quatromoni, E. Suzuki, O. Okusanya et al., "The timing of TGF-inhibition affects the generation of antigen-specific CD8+ T Cells, " BMC Immunology, vol. 14, no. 1, article 30, 2013.
155. D. Javelaud, K. S. Mohammad, C. R. McKenna et al., "Stable overexpression of Smad7 in human melanoma cells impairs bone metastasis, " Cancer Research, vol. 67, no. 5, pp. 2317-2324, 2007.
156. Y. Kang, W. He, S. Tulley et al., "Breast cancer bone metastasis mediated by the Smad tumor suppressor pathway, " Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 39, pp. 13909-13914, 2005.
157. L. Losi, H. Bouzourene, and J. Benhattar, "Loss of Smad4 expression predicts livermetastasis in human colorectal cancer, " Oncology Reports, vol. 17, no. 5, pp. 1095-1099, 2007.
158. M. Miyaki, T. Iijima, M. Konishi et al., "Higher frequency of Smad4 gene mutation in human colorectal cancer with distant metastasis, " Oncogene, vol. 18, no. 20, pp. 3098-3103, 1999.
159. E. C. Connolly, J. Freimuth, and R. J. Akhurst, "Complexities of TGF-targeted cancer therapy, " International Journal of Biological Sciences, vol. 8, no. 7, pp. 964-978, 2012.
160. N. S. Nagaraj and P. K. Datta, "Targeting the transforming growth factor-signaling pathway in human cancer, " Expert Opinion on InvestigationalDrugs, vol. 19, no. 1, pp. 77-91, 2010.