Immune checkpoints and their inhibition in cancer and infectious diseases

European Journal of Immunology

Volumn 47, Issue 5, 2017, Pages 765-779

  Dyck, Lydia ^a   Mills, Kingston H G ^a  

^a TRINITY COLLEGE DUBLIN   (Ireland)

Author keywords

Cancer; Immune checkpoint; Immunotherapy; Infection; Treg cells; Vaccine

Indexed keywords

CYTOTOXIC T LYMPHOCYTE ANTIGEN 4; CTLA4 PROTEIN, HUMAN; MONOCLONAL ANTIBODY; PDCD1 PROTEIN, HUMAN; PROGRAMMED DEATH 1 RECEPTOR; VACCINE;

ANTIGEN BINDING; ANTIGEN PRESENTING CELL; BACTERIAL INFECTION; BLADDER; CANCER PROGNOSIS; CANCER THERAPY; EFFECTOR CELL; EX VIVO STUDY; HUMAN; HUMAN IMMUNODEFICIENCY VIRUS; IMMUNOREGULATION; MALARIA; MALIGNANT NEOPLASM; MELANOMA; NATURAL KILLER CELL; NONHUMAN; PARASITOSIS; PREDICTIVE VALUE; PRIORITY JOURNAL; PROTEIN BINDING; REGULATORY T LYMPHOCYTE; REVIEW; SIGNAL TRANSDUCTION; TUBERCULOSIS; VIRUS INFECTION; ANTAGONISTS AND INHIBITORS; CD8+ T LYMPHOCYTE; CELL CYCLE CHECKPOINT; IMMUNOLOGY; IMMUNOTHERAPY; INFECTION; NEOPLASM; PHYSIOLOGY;

ANTIBODIES, MONOCLONAL; ANTIGEN-PRESENTING CELLS; CD8-POSITIVE T-LYMPHOCYTES; CELL CYCLE CHECKPOINTS; CTLA-4 ANTIGEN; HUMANS; IMMUNOTHERAPY; INFECTION; MELANOMA; NEOPLASMS; PROGRAMMED CELL DEATH 1 RECEPTOR; T-LYMPHOCYTES, REGULATORY; VACCINES;

EID: 85018516222     PISSN: 00142980     EISSN: 15214141     Source Type: Journal    
DOI: 10.1002/eji.201646875     Document Type: Review

References (169)

1. Pauken, K. E. and Wherry, E. J., Overcoming T cell exhaustion in infection and cancer. Trends Immunol. 2015. 36: 265–276.
2. Butt, A. Q. and Mills, K. H., Immunosuppressive networks and checkpoints controlling antitumor immunity and their blockade in the development of cancer immunotherapeutics and vaccines. Oncogene 2013. 33: 4623–4631.
3. Wherry, E. J. and Kurachi, M., Molecular and cellular insights into T cell exhaustion. Nat. Rev. Immunol. 2015. 15: 486–499.
4. Blackburn, S. D., Shin, H., Haining, W. N., Zou, T., Workman, C. J., Polley, A., Betts, M. R. et al., Coregulation of CD8+ T cell exhaustion by multiple inhibitory receptors during chronic viral infection. Nat. Immunol. 2009. 10: 29–37.
5. Anderson, A. C., Joller, N. and Kuchroo, V. K., Lag-3, Tim-3, and TIGIT: co-inhibitory receptors with specialized functions in immune regulation. Immunity 2016. 44: 989–1004.
6. Topalian, S. L., Drake, C. G. and Pardoll, D. M., Targeting the PD-1/B7-H1(PD-L1) pathway to activate anti-tumor immunity. Curr. Opin. Immunol. 2012. 24: 207–212.
7. Linsley, P. S., Brady, W., Urnes, M., Grosmaire, L. S., Damle, N. K. and Ledbetter, J. A., CTLA-4 is a second receptor for the B cell activation antigen B7. J. Exp. Med. 1991. 174: 561–569.
8. van der Merwe, P. A., Bodian, D. L., Daenke, S., Linsley, P. and Davis, S. J., CD80 (B7-1) binds both CD28 and CTLA-4 with a low affinity and very fast kinetics. J. Exp. Med. 1997. 185: 393–403.
9. Alegre, M. L., Frauwirth, K. A. and Thompson, C. B., T-cell regulation by CD28 and CTLA-4. Nat. Rev. Immunol. 2001. 1: 220–228.
10. Masteller, E. L., Chuang, E., Mullen, A. C., Reiner, S. L. and Thompson, C. B., Structural analysis of CTLA-4 function in vivo. J. Immunol. 2000. 164: 5319–5327.
11. Magistrelli, G., Jeannin, P., Herbault, N., Benoit De Coignac, A., Gauchat, J. F., Bonnefoy, J. Y. and Delneste, Y., A soluble form of CTLA-4 generated by alternative splicing is expressed by nonstimulated human T cells. Eur. J. Immunol. 1999. 29: 3596–3602.
12. Ward, F. J., Dahal, L. N., Wijesekera, S. K., Abdul-Jawad, S. K., Kaewarpai, T., Xu, H., Vickers, M. A. et al., The soluble isoform of CTLA-4 as a regulator of T-cell responses. Eur. J. Immunol. 2013. 43: 1274–1285.
13. Takahashi, T., Tagami, T., Yamazaki, S., Uede, T., Shimizu, J., Sakaguchi, N., Mak, T. W. et al., Immunologic self-tolerance maintained by CD25(+)CD4(+) regulatory T cells constitutively expressing cytotoxic T lymphocyte-associated antigen 4. J. Exp. Med. 2000. 192: 303–310.
14. Jago, C. B., Yates, J., Camara, N. O., Lechler, R. I. and Lombardi, G., Differential expression of CTLA-4 among T cell subsets. Clin. Exp. Immunol. 2004. 136: 463–471.
15. Jain, N., Nguyen, H., Chambers, C. and Kang, J., Dual function of CTLA-4 in regulatory T cells and conventional T cells to prevent multiorgan autoimmunity. Proc. Natl. Acad. Sci. USA 2010. 107: 1524–1528.
16. Schneider, H., Downey, J., Smith, A., Zinselmeyer, B. H., Rush, C., Brewer, J. M., Wei, B. et al., Reversal of the TCR stop signal by CTLA-4. Science 2006. 313: 1972–1975.
17. Riley, J. L., Mao, M., Kobayashi, S., Biery, M., Burchard, J., Cavet, G., Gregson, B. P. et al., Modulation of TCR-induced transcriptional profiles by ligation of CD28, ICOS, and CTLA-4 receptors. Proc. Natl. Acad. Sci. USA 2002. 99: 11790–11795.
18. Krummel, M. F. and Allison, J. P., CTLA-4 engagement inhibits IL-2 accumulation and cell cycle progression upon activation of resting T cells. J. Exp. Med. 1996. 183: 2533–2540.
19. Wing, K., Onishi, Y., Prieto-Martin, P., Yamaguchi, T., Miyara, M., Fehervari, Z., Nomura, T. et al., CTLA-4 control over Foxp3+ regulatory T cell function. Science 2008. 322: 271–275.
20. Peggs, K. S., Quezada, S. A., Chambers, C. A., Korman, A. J. and Allison, J. P., Blockade of CTLA-4 on both effector and regulatory T cell compartments contributes to the antitumor activity of anti-CTLA-4 antibodies. J. Exp. Med. 2009. 206: 1717–1725.
21. Callahan, M. K., Postow, M. A. and Wolchok, J. D., Targeting T cell co-receptors for cancer therapy. Immunity 2016. 44: 1069–1078.
22. Latchman, Y., Wood, C. R., Chernova, T., Chaudhary, D., Borde, M., Chernova, I., Iwai, Y. et al., PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat. Immunol. 2001. 2: 261–268.
23. Freeman, G. J., Long, A. J., Iwai, Y., Bourque, K., Chernova, T., Nishimura, H., Fitz, L. J. et al., Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J. Exp. Med. 2000. 192: 1027–1034.
24. Curiel, T. J., Wei, S., Dong, H., Alvarez, X., Cheng, P., Mottram, P., Krzysiek, R. et al., Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat. Med. 2003. 9: 562–567.
25. Daley, D., Zambirinis, C. P., Seifert, L., Akkad, N., Mohan, N., Werba, G., Barilla, R. et al., gammadelta T cells support pancreatic oncogenesis by restraining alphabeta T cell activation. Cell 2016. 166: 1485–1499, e1415.
26. Iraolagoitia, X. L., Spallanzani, R. G., Torres, N. I., Araya, R. E., Ziblat, A., Domaica, C. I., Sierra, J. M. et al., NK cells restrain spontaneous antitumor CD8+ T cell priming through PD-1/PD-L1 interactions with dendritic cells. J. Immunol. 2016. 197: 953–961.
27. Liang, S. C., Greenwald, R. J., Latchman, Y. E., Rosas, L., Satoskar, A., Freeman, G. J. and Sharpe, A. H., PD-L1 and PD-L2 have distinct roles in regulating host immunity to cutaneous leishmaniasis. Eur. J. Immunol. 2006. 36: 58–64.
28. Karunarathne, D. S., Horne-Debets, J. M., Huang, J. X., Faleiro, R., Leow, C. Y., Amante, F., Watkins, T. S. et al., Programmed death-1 ligand 2-mediated regulation of the PD-L1 to PD-1 axis is essential for establishing CD4(+) T cell immunity. Immunity 2016. 45: 333–345.
29. Chemnitz, J. M., Parry, R. V., Nichols, K. E., June, C. H. and 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. 2004. 173: 945–954.
30. Sheppard, K. A., Fitz, L. J., Lee, J. M., Benander, C., George, J. A., Wooters, J., Qiu, Y. et al., PD-1 inhibits T-cell receptor induced phosphorylation of the ZAP70/CD3zeta signalosome and downstream signaling to PKCtheta. FEBS Lett. 2004. 574: 37–41.
31. Patsoukis, N., Brown, J., Petkova, V., Liu, F., Li, L. and Boussiotis, V. A., Selective effects of PD-1 on Akt and Ras pathways regulate molecular components of the cell cycle and inhibit T cell proliferation. Sci. Signal 2012. 5: ra46.
32. Quigley, M., Pereyra, F., Nilsson, B., Porichis, F., Fonseca, C., Eichbaum, Q., Julg, B. et al., Transcriptional analysis of HIV-specific CD8+ T cells shows that PD-1 inhibits T cell function by upregulating BATF. Nat. Med. 2010. 16: 1147–1151.
33. Li, J., Jie, H. B., Lei, Y., Gildener-Leapman, N., Trivedi, S., Green, T., Kane, L. P. et al., PD-1/SHP-2 inhibits Tc1/Th1 phenotypic responses and the activation of T cells in the tumor microenvironment. Cancer Res. 2015. 75: 508–518.
34. Scharping, N. E., Menk, A. V., Moreci, R. S., Whetstone, R. D., Dadey, R. E., Watkins, S. C., Ferris, R. L. et al., The tumor microenvironment represses T cell mitochondrial biogenesis to drive intratumoral T cell metabolic insufficiency and dysfunction. Immunity 2016. 45: 374–388.
35. Patsoukis, N., Bardhan, K., Chatterjee, P., Sari, D., Liu, B., Bell, L. N., Karoly, E. D. et al., PD-1 alters T-cell metabolic reprogramming by inhibiting glycolysis and promoting lipolysis and fatty acid oxidation. Nat. Commun. 2015. 6: 6692.
36. Bengsch, B., Johnson, A. L., Kurachi, M., Odorizzi, P. M., Pauken, K. E., Attanasio, J., Stelekati, E. 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 2016. 45: 358–373.
37. Francisco, L. M., Salinas, V. H., Brown, K. E., Vanguri, V. K., Freeman, G. J., Kuchroo, V. K. and Sharpe, A. H., PD-L1 regulates the development, maintenance, and function of induced regulatory T cells. J. Exp. Med. 2009. 206: 3015–3029.
38. Wang, L., Pino-Lagos, K., de Vries, V. C., Guleria, I., Sayegh, M. H. and Noelle, R. J., Programmed death 1 ligand signaling regulates the generation of adaptive Foxp3+CD4+ regulatory T cells. Proc. Natl. Acad. Sci. USA 2008. 105: 9331–9336.
39. Dyck, L., Wilk, M. M., Raverdeau, M., Misiak, A., Boon, L. and Mills, K. H. G., Anti-PD-1 inhibits Foxp3+ Treg cell conversion and unleashes intratumoural effector T cells thereby enhancing the efficacy of a cancer vaccine in a mouse model. Cancer Immunol. Immunother. 2016. 65: 1491–1498.
40. Schietinger, A., Philip, M., Krisnawan, V. E., Chiu, E. Y., Delrow, J. J., Basom, R. S., Lauer, P. et al., Tumor-specific T cell dysfunction is a dynamic antigen-driven differentiation program initiated early during tumorigenesis. Immunity 2016. 45: 389–401.
41. Huard, B., Prigent, P., Tournier, M., Bruniquel, D. and Triebel, F., CD4/major histocompatibility complex class II interaction analyzed with CD4– and lymphocyte activation gene-3 (LAG-3)-Ig fusion proteins. Eur. J. Immunol. 1995. 25: 2718–2721.
42. Kang, C. W., Dutta, A., Chang, L. Y., Mahalingam, J., Lin, Y. C., Chiang, J. M., Hsu, C. Y. et al., Apoptosis of tumor infiltrating effector TIM-3+CD8+ T cells in colon cancer. Sci. Rep. 2015. 5: 15659.
43. Chiba, S., Baghdadi, M., Akiba, H., Yoshiyama, H., Kinoshita, I., Dosaka-Akita, H., Fujioka, Y. et al., Tumor-infiltrating DCs suppress nucleic acid-mediated innate immune responses through interactions between the receptor TIM-3 and the alarmin HMGB1. Nat. Immunol. 2012. 13: 832–842.
44. Benson, D. M., Jr., Bakan, C. E., Mishra, A., Hofmeister, C. C., Efebera, Y., Becknell, B., Baiocchi, R. A. et al., The PD-1/PD-L1 axis modulates the natural killer cell versus multiple myeloma effect: a therapeutic target for CT-011, a novel monoclonal anti-PD-1 antibody. Blood 2010. 116: 2286–2294.
45. Alvarez, I. B., Pasquinelli, V., Jurado, J. O., Abbate, E., Musella, R. M., de la Barrera, S. S. and Garcia, V. E., Role played by the programmed death-1-programmed death ligand pathway during innate immunity against Mycobacterium tuberculosis. J. Infect. Dis. 2010. 202: 524–532.
46. Norris, S., Coleman, A., Kuri-Cervantes, L., Bower, M., Nelson, M. and Goodier, M. R., PD-1 expression on natural killer cells and CD8(+) T cells during chronic HIV-1 infection. Viral Immunol. 2012. 25: 329–332.
47. Bottino, C., Castriconi, R., Pende, D., Rivera, P., Nanni, M., Carnemolla, B., Cantoni, C. et al., Identification of PVR (CD155) and Nectin-2 (CD112) as cell surface ligands for the human DNAM-1 (CD226) activating molecule. J. Exp. Med. 2003. 198: 557–567.
48. Stanietsky, N., Rovis, T. L., Glasner, A., Seidel, E., Tsukerman, P., Yamin, R., Enk, J. et al., Mouse TIGIT inhibits NK-cell cytotoxicity upon interaction with PVR. Eur. J. Immunol. 2013. 43: 2138–2150.
49. da Silva, I. P., Gallois, A., Jimenez-Baranda, S., Khan, S., Anderson, A. C., Kuchroo, V. K., Osman, I. et al., Reversal of NK-cell exhaustion in advanced melanoma by Tim-3 blockade. Cancer Immunol. Res. 2014. 2: 410–422.
50. Chen, D. S. and Mellman, I., Oncology meets immunology: the cancer-immunity cycle. Immunity 2013. 39: 1–10.
51. Apetoh, L., Smyth, M. J., Drake, C. G., Abastado, J. P., Apte, R. N., Ayyoub, M., Blay, J. Y. et al., Consensus nomenclature for CD8 T cell phenotypes in cancer. Oncoimmunology 2015. 4: e998538.
52. Nakano, O., Sato, M., Naito, Y., Suzuki, K., Orikasa, S., Aizawa, M., Suzuki, Y. et al., Proliferative activity of intratumoral CD8(+) T-lymphocytes as a prognostic factor in human renal cell carcinoma: clinicopathologic demonstration of antitumor immunity. Cancer Res. 2001. 61: 5132–5136.
53. Zhang, L., Conejo-Garcia, J. R., Katsaros, D., Gimotty, P. A., Massobrio, M., Regnani, G., Makrigiannakis, A. et al., Intratumoral T cells, recurrence, and survival in epithelial ovarian cancer. N. Engl. J. Med. 2003. 348: 203–213.
54. Diederichsen, A. C., Hjelmborg, J., Christensen, P. B., Zeuthen, J. and Fenger, C., Prognostic value of the CD4+/CD8+ ratio of tumour infiltrating lymphocytes in colorectal cancer and HLA-DR expression on tumour cells. Cancer Immunol. Immunother. 2003. 52: 423–428.
55. Piras, F., Colombari, R., Minerba, L., Murtas, D., Floris, C., Maxia, C., Corbu, A. et al., The predictive value of CD8, CD4, CD68, and human leukocyte antigen-D-related cells in the prognosis of cutaneous malignant melanoma with vertical growth phase. Cancer 2005. 104: 1246–1254.
56. Mahmoud, S. M., Paish, E. C., Powe, D. G., Macmillan, R. D., Grainge, M. J., Lee, A. H., Ellis, I. O. et al., Tumor-infiltrating CD8+ lymphocytes predict clinical outcome in breast cancer. J. Clin. Oncol. 2011. 29: 1949–1955.
57. Liu, S., Lachapelle, J., Leung, S., Gao, D., Foulkes, W. D. and Nielsen, T. O., CD8+ lymphocyte infiltration is an independent favorable prognostic indicator in basal-like breast cancer. Breast Cancer Res. 2012. 14: R48.
58. Galon, J., Costes, A., Sanchez-Cabo, F., Kirilovsky, A., Mlecnik, B., Lagorce-Pages, C., Tosolini, M. et al., Type, density, and location of immune cells within human colorectal tumors predict clinical outcome. Science 2006. 313: 1960–1964.
59. Dieu-Nosjean, M. C., Antoine, M., Danel, C., Heudes, D., Wislez, M., Poulot, V., Rabbe, N. et al., Long-term survival for patients with non-small-cell lung cancer with intratumoral lymphoid structures. J. Clin. Oncol. 2008. 26: 4410–4417.
60. Giraldo, N. A., Becht, E., Pages, F., Skliris, G., Verkarre, V., Vano, Y., Mejean, A. et al., Orchestration and prognostic significance of immune checkpoints in the microenvironment of primary and metastatic renal cell cancer. Clin. Cancer Res. 2015. 21: 3031–3040.
61. Tjin, E. P., Krebbers, G., Meijlink, K. J., van de Kasteele, W., Rosenberg, E. H., Sanders, J., Nederlof, P. M. et al., Immune-escape markers in relation to clinical outcome of advanced melanoma patients following immunotherapy. Cancer Immunol. Res. 2014. 2: 538–546.
62. Miyashita, M., Sasano, H., Tamaki, K., Hirakawa, H., Takahashi, Y., Nakagawa, S., Watanabe, G. et al., Prognostic significance of tumor-infiltrating CD8+ and FOXP3+ lymphocytes in residual tumors and alterations in these parameters after neoadjuvant chemotherapy in triple-negative breast cancer: a retrospective multicenter study. Breast Cancer Res. 2015. 17: 124.
63. Lysaght, J., Jarnicki, A. G. and Mills, K. H., Reciprocal effects of Th1 and Treg cell inducing pathogen-associated immunomodulatory molecules on anti-tumor immunity. Cancer Immunol. Immunother. 2007. 56: 1367–1379.
64. Jarnicki, A. G., Lysaght, J., Todryk, S. and Mills, K. H., Suppression of antitumor immunity by IL-10 and TGF-beta-producing T cells infiltrating the growing tumor: influence of tumor environment on the induction of CD4+ and CD8+ regulatory T cells. J. Immunol. 2006. 177: 896–904.
65. Turk, M. J., Guevara-Patino, J. A., Rizzuto, G. A., Engelhorn, M. E., Sakaguchi, S. and Houghton, A. N., Concomitant tumor immunity to a poorly immunogenic melanoma is prevented by regulatory T cells. J. Exp. Med. 2004. 200: 771–782.
66. Akeus, P., Langenes, V., Kristensen, J., von Mentzer, A., Sparwasser, T., Raghavan, S. and Quiding-Jarbrink, M., Treg-cell depletion promotes chemokine production and accumulation of CXCR3(+) conventional T cells in intestinal tumors. Eur. J. Immunol. 2015. 45: 1654–1666.
67. Sato, E., Olson, S. H., Ahn, J., Bundy, B., Nishikawa, H., Qian, F., Jungbluth, A. A. et al., Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. Proc. Natl. Acad. Sci. USA 2005. 102: 18538–18543.
68. Gao, Q., Qiu, S. J., Fan, J., Zhou, J., Wang, X. Y., Xiao, Y. S., Xu, Y. et al., Intratumoral balance of regulatory and cytotoxic T cells is associated with prognosis of hepatocellular carcinoma after resection. J. Clin. Oncol. 2007. 25: 2586–2593.
69. Angelova, M., Charoentong, P., Hackl, H., Fischer, M. L., Snajder, R., Krogsdam, A. M., Waldner, M. J. et al., Characterization of the immunophenotypes and antigenomes of colorectal cancers reveals distinct tumor escape mechanisms and novel targets for immunotherapy. Genome. Biol. 2015. 16: 64.
70. Liu, C., Workman, C. J. and Vignali, D. A., Targeting regulatory T cells in tumors. FEBS J. 2016. 283: 2731–2748.
71. Facciabene, A., Peng, X., Hagemann, I. S., Balint, K., Barchetti, A., Wang, L. P., Gimotty, P. A. et al., Tumour hypoxia promotes tolerance and angiogenesis via CCL28 and T(reg) cells. Nature 2011. 475: 226–230.
72. Chang, D. K., Peterson, E., Sun, J., Goudie, C., Drapkin, R. I., Liu, J. F., Matulonis, U. et al., Anti-CCR4 monoclonal antibody enhances antitumor immunity by modulating tumor-infiltrating Tregs in an ovarian cancer xenograft humanized mouse model. Oncoimmunology 2016. 5: e1090075.
73. Sugiyama, D., Nishikawa, H., Maeda, Y., Nishioka, M., Tanemura, A., Katayama, I., Ezoe, S. et al., Anti-CCR4 mAb selectively depletes effector-type FoxP3+CD4+ regulatory T cells, evoking antitumor immune responses in humans. Proc. Natl. Acad. Sci. USA 2013. 110: 17945–17950.
74. Galvin, K. C., Dyck, L., Marshall, N. A., Stefanska, A. M., Walsh, K. P., Moran, B., Higgins, S. C. et al., Blocking retinoic acid receptor-α enhances the efficacy of a dendritic cell vaccine against tumours by suppressing the induction of regulatory T cells. Cancer Immunol. Immunother. 2013. 62: 1273–1282.
75. Maldonado, R. A. and von Andrian, U. H., How tolerogenic dendritic cells induce regulatory T cells. Adv. Immunol. 2010. 108: 111–165.
76. Ghiringhelli, F., Puig, P. E., Roux, S., Parcellier, A., Schmitt, E., Solary, E., Kroemer, G. et al., Tumor cells convert immature myeloid dendritic cells into TGF-beta-secreting cells inducing CD4+CD25+ regulatory T cell proliferation. J. Exp. Med. 2005. 202: 919–929.
77. Nishikawa, H. and Sakaguchi, S., Regulatory T cells in cancer immunotherapy. Curr. Opin. Immunol. 2014. 27: 1–7.
78. Fourcade, J., Sun, Z., Kudela, P., Janjic, B., Kirkwood, J. M., El-Hafnawy, T. and Zarour, H. M., Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire. J. Immunol. 2010. 184: 6709–6718.
79. Bonertz, A., Weitz, J., Pietsch, D. H., Rahbari, N. N., Schlude, C., Ge, Y., Juenger, S. et al., Antigen-specific Tregs control T cell responses against a limited repertoire of tumor antigens in patients with colorectal carcinoma. J. Clin. Invest. 2009. 119: 3311–3321.
80. Nishikawa, H. and Sakaguchi, S., Regulatory T cells in tumor immunity. Int. J. Cancer 2010. 127: 759–767.
81. Riches, J. C., Davies, J. K., McClanahan, F., Fatah, R., Iqbal, S., Agrawal, S., Ramsay, A. G. et al., T cells from CLL patients exhibit features of T-cell exhaustion but retain capacity for cytokine production. Blood 2013. 121: 1612–1621.
82. Matsuzaki, J., Gnjatic, S., Mhawech-Fauceglia, P., Beck, A., Miller, A., Tsuji, T., Eppolito, C. 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 2010. 107: 7875–7880.
83. Zhang, Y., Huang, S., Gong, D., Qin, Y. and Shen, Q., Programmed death-1 upregulation is correlated with dysfunction of tumor-infiltrating CD8+ T lymphocytes in human non-small cell lung cancer. Cell Mol. Immunol. 2010. 7: 389–395.
84. Ahmadzadeh, M., Johnson, L. A., Heemskerk, B., Wunderlich, J. R., Dudley, M. E., White, D. E. and Rosenberg, S. A., Tumor antigen-specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood 2009. 114: 1537–1544.
85. Fourcade, J., Sun, Z., Benallaoua, M., Guillaume, P., Luescher, I. F., Sander, C., Kirkwood, J. M. 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. 2010. 207: 2175–2186.
86. Zhang, Y., Kang, S., Shen, J., He, J., Jiang, L., Wang, W., Guo, Z. et al., Prognostic significance of programmed cell death 1 (PD-1) or PD-1 ligand 1 (PD-L1) expression in epithelial-originated cancer: a meta-analysis. Medicine (Baltimore) 2015. 94: e515.
87. Kataoka, K., Shiraishi, Y., Takeda, Y., Sakata, S., Matsumoto, M., Nagano, S., Maeda, T. et al., Aberrant PD-L1 expression through 3'-UTR disruption in multiple cancers. Nature 2016. 534: 402–406.
88. Massi, D., Brusa, D., Merelli, B., Ciano, M., Audrito, V., Serra, S., Buonincontri, R. et al., PD-L1 marks a subset of melanomas with a shorter overall survival and distinct genetic and morphological characteristics. Ann. Oncol. 2014. 25: 2433–2442.
89. Leite, K. R., Reis, S. T., Junior, J. P., Zerati, M., Gomes Dde, O., Camara-Lopes, L. H. and Srougi, M., PD-L1 expression in renal cell carcinoma clear cell type is related to unfavorable prognosis. Diagn. Pathol. 2015. 10: 189.
90. Jung, H. I., Jeong, D., Ji, S., Ahn, T. S., Bae, S. H., Chin, S., Chung, J. C. et al., Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res. Treat. 2016. 49: 246–254.
91. Ameratunga, M., Asadi, K., Lin, X., Walkiewicz, M., Murone, C., Knight, S., Mitchell, P. et al., PD-L1 and Tumor infiltrating lymphocytes as prognostic markers in resected NSCLC. PLoS One 2016. 11: e0153954.
92. Sorensen, S. F., Zhou, W., Dolled-Filhart, M., Georgsen, J. B., Wang, Z., Emancipator, K., Wu, D. et al., PD-L1 expression and survival among patients with advanced non-small cell lung cancer treated with chemotherapy. Transl. Oncol. 2016. 9: 64–69.
93. Dunne, P. D., McArt, D. G., O'Reilly, P. G., Coleman, H. G., Allen, W. L., Loughrey, M., Van Schaeybroeck, S. et al., Immune-derived PD-L1 gene expression defines a subgroup of stage II/III Colorectal Cancer patients with favorable prognosis who may be harmed by adjuvant chemotherapy. Cancer Immunol. Res. 2016. 4: 582–591.
94. Baptista, M. Z., Sarian, L. O., Derchain, S. F., Pinto, G. A. and Vassallo, J., Prognostic significance of PD-L1 and PD-L2 in breast cancer. Hum. Pathol. 2016. 47: 78–84.
95. Huang, P. Y., Guo, S. S., Zhang, Y., Lu, J. B., Chen, Q. Y., Tang, L. Q., Zhang, L. et al., Tumor CTLA-4 overexpression predicts poor survival in patients with nasopharyngeal carcinoma. Oncotarget 2016. 7: 13060–13068.
96. Mao, H., Zhang, L., Yang, Y., Zuo, W., Bi, Y., Gao, W., Deng, B. et al., New insights of CTLA-4 into its biological function in breast cancer. Curr. Cancer Drug Targets 2010. 10: 728–736.
97. Salvi, S., Fontana, V., Boccardo, S., Merlo, D. F., Margallo, E., Laurent, S., Morabito, A. et al., Evaluation of CTLA-4 expression and relevance as a novel prognostic factor in patients with non-small cell lung cancer. Cancer Immunol. Immunother. 2012. 61: 1463–1472.
98. Joshi, A. D., Hegde, G. V., Dickinson, J. D., Mittal, A. K., Lynch, J. C., Eudy, J. D., Armitage, J. O. et al., ATM, CTLA4, MNDA, and HEM1 in high versus low CD38 expressing B-cell chronic lymphocytic leukemia. Clin. Cancer Res. 2007. 13: 5295–5304.
99. Ai, M. and Curran, M. A., Immune checkpoint combinations from mouse to man. Cancer Immunol. Immunother. 2015. 64: 885–892.
100. van Elsas, A., Hurwitz, A. A. and Allison, J. P., Combination immunotherapy of B16 melanoma using anti-cytotoxic T lymphocyte-associated antigen 4 (CTLA-4) and granulocyte/macrophage colony-stimulating factor (GM-CSF)-producing vaccines induces rejection of subcutaneous and metastatic tumors accompanied by autoimmune depigmentation. J. Exp. Med. 1999. 190: 355–366.
101. Duraiswamy, J., Kaluza, K. M., Freeman, G. J. and Coukos, G., Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. Cancer Res. 2013. 73: 3591–3603.
102. Hodi, F. S., O'Day, S. J., McDermott, D. F., Weber, R. W., Sosman, J. A., Haanen, J. B., Gonzalez, R. et al., Improved survival with ipilimumab in patients with metastatic melanoma. N. Engl. J. Med. 2010. 363: 711–723.
103. Robert, C., Thomas, L., Bondarenko, I., O'Day, S., Weber, J., Garbe, C., Lebbe, C. et al., Ipilimumab plus dacarbazine for previously untreated metastatic melanoma. N. Engl. J. Med. 2011. 364: 2517–2526.
104. Ribas, A. and Flaherty, K. T., Gauging the long-term benefits of ipilimumab in melanoma. J. Clin. Oncol. 2015. 33: 1865–1866.
105. Duraiswamy, J., Freeman, G. J. and Coukos, G., Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. Cancer Res. 2013. 73: 6900–6912.
106. Sakuishi, K., Apetoh, L., Sullivan, J. M., Blazar, B. R., Kuchroo, V. K. and Anderson, A. C., Targeting Tim-3 and PD-1 pathways to reverse T cell exhaustion and restore anti-tumor immunity. J. Exp. Med. 2010. 207: 2187–2194.
107. Curran, M. A., Montalvo, W., Yagita, H. and Allison, J. P., PD-1 and CTLA-4 combination blockade expands infiltrating T cells and reduces regulatory T and myeloid cells within B16 melanoma tumors. Proc. Natl. Acad. Sci. USA 2010. 107: 4275–4280.
108. Woo, S. R., Turnis, M. E., Goldberg, M. V., Bankoti, J., Selby, M., Nirschl, C. J., Bettini, M. L. et al., Immune inhibitory molecules LAG-3 and PD-1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. 2012. 72: 917–927.
109. Peng, W., Liu, C., Xu, C., Lou, Y., Chen, J., Yang, Y., Yagita, H. et al., PD-1 blockade enhances T-cell migration to tumors by elevating IFN-gamma inducible chemokines. Cancer Res. 2012. 72: 5209–5218.
110. Robert, C., Ribas, A., Wolchok, J. D., Hodi, F. S., Hamid, O., Kefford, R., Weber, J. S. et al., Anti-programmed-death-receptor-1 treatment with pembrolizumab in ipilimumab-refractory advanced melanoma: a randomised dose-comparison cohort of a phase 1 trial. Lancet 2014. 384: 1109–1117.
111. Garon, E. B., Rizvi, N. A., Hui, R., Leighl, N., Balmanoukian, A. S., Eder, J. P., Patnaik, A. et al., Pembrolizumab for the treatment of non-small-cell lung cancer. N. Engl. J. Med. 2015. 372: 2018–2028.
112. First-line atezolizumab effective in bladder cancer. Cancer Discov. 2016. 8.
113. Robert, C., Schachter, J., Long, G. V., Arance, A., Grob, J. J., Mortier, L., Daud, A. et al., Pembrolizumab versus ipilimumab in advanced melanoma. N. Engl. J. Med. 2015. 372: 2521–2532.
114. Larkin, J., Chiarion-Sileni, V., Gonzalez, R., Grob, J. J., Cowey, C. L., Lao, C. D., Schadendorf, D. et al., Combined nivolumab and ipilimumab or monotherapy in untreated melanoma. N. Engl. J. Med. 2015. 373: 23–34.
115. Shreders, A., Joseph, R., Peng, C., Ye, F., Zhao, S., Puzanov, I., Sosman, J. A. et al., Prolonged benefit from Ipilimumab correlates with improved outcomes from subsequent pembrolizumab. Cancer Immunol. Res. 2016. 4: 569–573.
116. Buchbinder, E. I. and Desai, A., CTLA-4 and PD-1 pathways: similarities, differences, and implications of their inhibition. Am. J. Clin. Oncol. 2016. 39: 98–106.
117. Grosso, J. F., Kelleher, C. C., Harris, T. J., Maris, C. H., Hipkiss, E. L., De Marzo, A., Anders, R. et al., LAG-3 regulates CD8+ T cell accumulation and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. 2007. 117: 3383–3392.
118. Ngiow, S. F., von Scheidt, B., Akiba, H., Yagita, H., Teng, M. W. and Smyth, M. J., Anti-TIM3 antibody promotes T cell IFN-gamma-mediated antitumor immunity and suppresses established tumors. Cancer Res. 2011. 71: 3540–3551.
119. Zhou, Q., Munger, M. E., Veenstra, R. G., Weigel, B. J., Hirashima, M., Munn, D. H., Murphy, W. J. et al., Coexpression of Tim-3 and PD-1 identifies a CD8+ T-cell exhaustion phenotype in mice with disseminated acute myelogenous leukemia. Blood 2011. 117: 4501–4510.
120. Kurtulus, S., Sakuishi, K., Ngiow, S. F., Joller, N., Tan, D. J., Teng, M. W., Smyth, M. J. et al., TIGIT predominantly regulates the immune response via regulatory T cells. J. Clin. Invest. 2015. 125: 4053–4062.
121. Shindo, Y., Yoshimura, K., Kuramasu, A., Watanabe, Y., Ito, H., Kondo, T., Oga, A. et al., Combination immunotherapy with 4-1BB activation and PD-1 blockade enhances antitumor efficacy in a mouse model of subcutaneous tumor. Anticancer Res. 2015. 35: 129–136.
122. Ali, O. A., Lewin, S. A., Dranoff, G. and Mooney, D. J., Vaccines combined with immune checkpoint antibodies promote cytotoxic T-cell activity and tumor eradication. Cancer Immunol. Res. 2016. 4: 95–100.
123. Twyman-Saint\sVictor, C., Rech, A. J., Maity, A., Rengan, R., Pauken, K. E., Stelekati, E., Benci, J. L. et al., Radiation and dual checkpoint blockade activate non-redundant immune mechanisms in cancer. Nature 2015. 520: 373–377.
124. Shi, L., Chen, L., Wu, C., Zhu, Y., Xu, B., Zheng, X., Sun, M. et al., PD-1 blockade boosts radiofrequency ablation-elicited adaptive immune responses against tumor. Clin. Cancer Res. 2016. 22: 1173–1184.
125. Ebert, P. J., Cheung, J., Yang, Y., McNamara, E., Hong, R., Moskalenko, M., Gould, S. E. et al., MAP Kinase inhibition promotes T cell and anti-tumor activity in combination with PD-L1 checkpoint blockade. Immunity 2016. 44: 609–621.
126. Woods, D. M., Woan, K., Cheng, F., Wang, H., Perez-Villarroel, P., Lee, C., Lienlaf, M. et al., The antimelanoma activity of the histone deacetylase inhibitor panobinostat (LBH589) is mediated by direct tumor cytotoxicity and increased tumor immunogenicity. Melanoma. Res. 2013. 23: 341–348.
127. Woods, D. M., Sodre, A. L., Villagra, A., Sarnaik, A., Sotomayor, E. M. and Weber, J., HDAC inhibition upregulates PD-1 ligands in melanoma and augments immunotherapy with PD-1 blockade. Cancer Immunol. Res. 2015. 3: 1375–1385.
128. Zheng, H., Zhao, W., Yan, C., Watson, C. C., Massengill, M., Xie, M., Massengill, C. et al., HDAC inhibitors enhance T-cell chemokine expression and augment response to PD-1 immunotherapy in lung adenocarcinoma. Clin. Cancer Res. 2016. 22: 4119–4132.
129. Barber, D. L., Wherry, E. J., Masopust, D., Zhu, B., Allison, J. P., Sharpe, A. H., Freeman, G. J. et al., Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 2006. 439: 682–687.
130. Wherry, E. J., Blattman, J. N., Murali-Krishna, K., van der Most, R. and Ahmed, R., Viral persistence alters CD8 T-cell immunodominance and tissue distribution and results in distinct stages of functional impairment. J. Virol. 2003. 77: 4911–4927.
131. Ha, S. J., Mueller, S. N., Wherry, E. J., Barber, D. L., Aubert, R. D., Sharpe, A. H., Freeman, G. J. et al., Enhancing therapeutic vaccination by blocking PD-1-mediated inhibitory signals during chronic infection. J. Exp. Med. 2008. 205: 543–555.
132. Day, C. L., Kaufmann, D. E., Kiepiela, P., Brown, J. A., Moodley, E. S., Reddy, S., Mackey, E. W. et al., PD-1 expression on HIV-specific T cells is associated with T-cell exhaustion and disease progression. Nature 2006. 443: 350–354.
133. Petrovas, C., Casazza, J. P., Brenchley, J. M., Price, D. A., Gostick, E., Adams, W. C., Precopio, M. L. et al., PD-1 is a regulator of virus-specific CD8+ T cell survival in HIV infection. J. Exp. Med. 2006. 203: 2281–2292.
134. Zhang, J. Y., Zhang, Z., Wang, X., Fu, J. L., Yao, J., Jiao, Y., Chen, L. et al., PD-1 up-regulation is correlated with HIV-specific memory CD8+ T-cell exhaustion in typical progressors but not in long-term nonprogressors. Blood 2007. 109: 4671–4678.
135. Gill, A. L., Green, S. A., Abdullah, S., Le Saout, C., Pittaluga, S., Chen, H., Turnier, R. et al., Programed death-1/programed death-ligand 1 expression in lymph nodes of HIV infected patients: results of a pilot safety study in rhesus macaques using anti-programed death-ligand 1 (Avelumab). AIDS 2016. 30: 2487–2493.
136. Chew, G. M., Fujita, T., Webb, G. M., Burwitz, B. J., Wu, H. L., Reed, J. S., Hammond, K. B. et al., TIGIT marks exhausted T cells, correlates with disease progression, and serves as a target for immune restoration in HIV and SIV infection. PLoS Pathog. 2016. 12: e1005349.
137. Pauken, K. E. and Wherry, E. J., TIGIT and CD226: tipping the balance between costimulatory and coinhibitory molecules to augment the cancer immunotherapy toolkit. Cancer Cell 2014. 26: 785–787.
138. Eron, J. J., Gay, C., Bosch, R., Ritz, J., Hataye, J. M., Hwang, C., Tressler, R. L. et al., Safety, immunologic and virologic activity of anti-PD-L1 in HIV-1 participants on ART. Abstract 25. Conference on Retroviruses and Opportunistic Infections CROI, Boston, MA, 22–25 February 2016.
139. Peng, G., Li, S., Wu, W., Tan, X., Chen, Y. and Chen, Z., PD-1 upregulation is associated with HBV-specific T cell dysfunction in chronic hepatitis B patients. Mol. Immunol. 2008. 45: 963–970.
140. Evans, A., Riva, A., Cooksley, H., Phillips, S., Puranik, S., Nathwani, A., Brett, S. et al., Programmed death 1 expression during antiviral treatment of chronic hepatitis B: impact of hepatitis B e-antigen seroconversion. Hepatology 2008. 48: 759–769.
141. Tang, Z. S., Hao, Y. H., Zhang, E. J., Xu, C. L., Zhou, Y., Zheng, X. and Yang, D. L., CD28 family of receptors on T cells in chronic HBV infection: expression characteristics, clinical significance and correlations with PD-1 blockade. Mol. Med. Rep. 2016. 14: 1107–1116.
142. Wu, W., Shi, Y., Li, S., Zhang, Y., Liu, Y., Wu, Y. and Chen, Z., Blockade of Tim-3 signaling restores the virus-specific CD8(+) T-cell response in patients with chronic hepatitis B. Eur. J. Immunol. 2012. 42: 1180–1191.
143. Salem, M. L. and El-Badawy, A., Programmed death-1/programmed death-L1 signaling pathway and its blockade in hepatitis C virus immunotherapy. World J. Hepatol. 2015. 7: 2449–2458.
144. Fuller, M. J., Callendret, B., Zhu, B., Freeman, G. J., Hasselschwert, D. L., Satterfield, W., Sharpe, A. H. et al., Immunotherapy of chronic hepatitis C virus infection with antibodies against programmed cell death-1 (PD-1). Proc. Natl. Acad. Sci. USA 2013. 110: 15001–15006.
145. Gardiner, D., Lalezari, J., Lawitz, E., DiMicco, M., Ghalib, R., Reddy, K. R., Chang, K. M. et al., A randomized, double-blind, placebo-controlled assessment of BMS-936558, a fully human monoclonal antibody to programmed death-1 (PD-1), in patients with chronic hepatitis C virus infection. PLoS One 2013. 8: e63818.
146. McMichael, A. J., Gotch, F. M., Noble, G. R. and Beare, P. A., Cytotoxic T-cell immunity to influenza. N. Engl. J. Med. 1983. 309: 13–17.
147. Rutigliano, J. A., Sharma, S., Morris, M. Y., Oguin, T. H., 3rd, McClaren, J. L., Doherty, P. C. and Thomas, P. G., Highly pathological influenza A virus infection is associated with augmented expression of PD-1 by functionally compromised virus-specific CD8+ T cells. J. Virol. 2014. 88: 1636–1651.
148. Bucks, C. M., Norton, J. A., Boesteanu, A. C., Mueller, Y. M. and Katsikis, P. D., Chronic antigen stimulation alone is sufficient to drive CD8+ T cell exhaustion. J. Immunol. 2009. 182: 6697–6708.
149. Finlay, C. M., Walsh, K. P. and Mills, K. H., Induction of regulatory cells by helminth parasites: exploitation for the treatment of inflammatory diseases. Immunol. Rev. 2014. 259: 206–230.
150. Joshi, T., Rodriguez, S., Perovic, V., Cockburn, I. A. and Stager, S., B7-H1 blockade increases survival of dysfunctional CD8(+) T cells and confers protection against Leishmania donovani infections. PLoS Pathog. 2009. 5: e1000431.
151. Hernandez-Ruiz, J., Salaiza-Suazo, N., Carrada, G., Escoto, S., Ruiz-Remigio, A., Rosenstein, Y., Zentella, A. et al., CD8 cells of patients with diffuse cutaneous leishmaniasis display functional exhaustion: the latter is reversed, in vitro, by TLR2 agonists. PLoS Negl. Trop. Dis. 2010. 4: e871.
152. Gao, Y., Chen, L., Hou, M., Chen, Y., Ji, M., Wu, H. and Wu, G., TLR2 directing PD-L2 expression inhibit T cells response in Schistosoma japonicum infection. PLoS One 2013. 8: e82480.
153. Hafalla, J. C., Claser, C., Couper, K. N., Grau, G. E., Renia, L., de Souza, J. B. and Riley, E. M., The CTLA-4 and PD-1/PD-L1 inhibitory pathways independently regulate host resistance to Plasmodium-induced acute immune pathology. PLoS Pathog. 2012. 8: e1002504.
154. Murphy, M. L., Cotterell, S. E., Gorak, P. M., Engwerda, C. R. and Kaye, P. M., Blockade of CTLA-4 enhances host resistance to the intracellular pathogen, Leishmania donovani. J. Immunol. 1998. 161: 4153–4160.
155. Gomes, N. A., Gattass, C. R., Barreto-De-Souza, V., Wilson, M. E. and DosReis, G. A., TGF-beta mediates CTLA-4 suppression of cellular immunity in murine kalaazar. J. Immunol. 2000. 164: 2001–2008.
156. Bhadra, R., Gigley, J. P., Weiss, L. M. and Khan, I. A., Control of Toxoplasma reactivation by rescue of dysfunctional CD8+ T-cell response via PD-1-PDL-1 blockade. Proc. Natl. Acad. Sci. USA 2011. 108: 9196–9201.
157. Butler, N. S., Moebius, J., Pewe, L. L., Traore, B., Doumbo, O. K., Tygrett, L. T., Waldschmidt, T. J. et al., Therapeutic blockade of PD-L1 and LAG-3 rapidly clears established blood-stage Plasmodium infection. Nat. Immunol. 2012. 13: 188–195.
158. Doe, H. T., Kimura, D., Miyakoda, M., Kimura, K., Akbari, M. and Yui, K., Expression of PD-1/LAG-3 and cytokine production by CD4(+) T cells during infection with Plasmodium parasites. Microbiol. Immunol. 2016. 60: 121–131.
159. Das, S., Suarez, G., Beswick, E. J., Sierra, J. C., Graham, D. Y. and Reyes, V. E., Expression of B7-H1 on gastric epithelial cells: its potential role in regulating T cells during Helicobacter pylori infection. J. Immunol. 2006. 176: 3000–3009.
160. Beswick, E. J., Pinchuk, I. V., Das, S., Powell, D. W. and Reyes, V. E., Expression of the programmed death ligand 1, B7-H1, on gastric epithelial cells after Helicobacter pylori exposure promotes development of CD4+ CD25+ FoxP3+ regulatory T cells. Infect. Immun. 2007. 75: 4334–4341.
161. McBerry, C., Dias, A., Shryock, N., Lampe, K., Gutierrez, F. R., Boon, L., De'Broski, R. H. et al., PD-1 modulates steady-state and infection-induced IL-10 production in vivo. Eur. J. Immunol. 2014. 44: 469–479.
162. Trinath, J., Maddur, M. S., Kaveri, S. V., Balaji, K. N. and Bayry, J., Mycobacterium tuberculosis promotes regulatory T-cell expansion via induction of programmed death-1 ligand 1 (PD-L1, CD274) on dendritic cells. J. Infect. Dis. 2012. 205: 694–696.
163. Lazar-Molnar, E., Chen, B., Sweeney, K. A., Wang, E. J., Liu, W., Lin, J., Porcelli, S. A. et al., Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc. Natl. Acad. Sci. USA 2010. 107: 13402–13407.
164. Sakai, S., Kauffman, K. D., Sallin, M. A., Sharpe, A. H., Young, H. A., Ganusov, V. V. and Barber, D. L., CD4 T cell-derived IFN-gamma plays a minimal role in control of pulmonary mycobacterium tuberculosis Infection and must be actively repressed by PD-1 to prevent lethal disease. PLoS Pathog. 2016. 12: e1005667.
165. Shen, L., Gao, Y., Liu, Y., Zhang, B., Liu, Q., Wu, J., Fan, L. et al., PD-1/PD-L pathway inhibits M.tb-specific CD4+ T-cell functions and phagocytosis of macrophages in active tuberculosis. Sci. Rep. 2016. 6: 38362.
166. Shen, L., Shi, H., Gao, Y., Ou, Q., Liu, Q., Liu, Y., Wu, J. et al., The characteristic profiles of PD-1 and PD-L1 expressions and dynamic changes during treatment in active tuberculosis. Tuberculosis (Edinb) 2016. 101: 146–150.
167. Mills, K. H., Regulatory T cells: friend or foe in immunity to infection? Nat. Rev. Immunol. 2004. 4: 841–855.
168. Jarnicki, A. G., Conroy, H., Brereton, C., Donnelly, G., Toomey, D., Walsh, K., Sweeney, C. et al., Attenuating regulatory T cell induction by TLR agonists through inhibition of p38 MAPK signaling in dendritic cells enhances their efficacy as vaccine adjuvants and cancer immunotherapeutics. J. Immunol. 2008. 180: 3797–3806.
169. Moore, A. C., Gallimore, A., Draper, S. J., Watkins, K. R., Gilbert, S. C. and Hill, A. V., Anti-CD25 antibody enhancement of vaccine-induced immunogenicity: increased durable cellular immunity with reduced immunodominance. J. Immunol. 2005. 175: 7264–7273.