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Published in: International Journal of Clinical Oncology 3/2016

01-06-2016 | Invited Review Article

Basics of PD-1 in self-tolerance, infection, and cancer immunity

Author: Shunsuke Chikuma

Published in: International Journal of Clinical Oncology | Issue 3/2016

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Abstract

Successful cancer treatment requires understanding host immune response against tumor cells. PD-1 belongs to the CD28 superfamily of receptors that work as “checkpoints” of immune activation. PD-1 maintains immune self-tolerance to prevent autoimmunity and controls T-cell reaction during infection to prevent excessive tissue damage. Tumor cells that arise from normal tissue acquire mutations that can be targeted by lymphocytes. Accumulating lines of evidence suggest that tumor cells evade host immune attack by expressing physiological PD-1 ligands and stimulating PD-1 on the lymphocytes. Based on this idea, researchers have successfully demonstrated that systemic administration of monoclonal antibodies that inhibit the binding of PD-1 to the ligands reactivated T cells and augmented the anti-cancer immune response. In this review, I summarize the basics of T-cell biology and its regulation by PD-1 and discuss the current understanding and questions about this multifaceted molecule.
Literature
1.
go back to reference Lenschow DJ, Walunas TL, Bluestone JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258CrossRefPubMed Lenschow DJ, Walunas TL, Bluestone JA (1996) CD28/B7 system of T cell costimulation. Annu Rev Immunol 14:233–258CrossRefPubMed
2.
go back to reference Bour-Jordan H, Esensten JH, Martinez-Llordella M et al (2011) Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev 241:180–205CrossRefPubMedPubMedCentral Bour-Jordan H, Esensten JH, Martinez-Llordella M et al (2011) Intrinsic and extrinsic control of peripheral T-cell tolerance by costimulatory molecules of the CD28/B7 family. Immunol Rev 241:180–205CrossRefPubMedPubMedCentral
3.
go back to reference Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465CrossRefPubMed Krummel MF, Allison JP (1995) CD28 and CTLA-4 have opposing effects on the response of T cells to stimulation. J Exp Med 182:459–465CrossRefPubMed
4.
go back to reference Walunas TL et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413CrossRefPubMed Walunas TL et al (1994) CTLA-4 can function as a negative regulator of T cell activation. Immunity 1:405–413CrossRefPubMed
5.
go back to reference Tivol EA, Borriello F, Schweitzer AN et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547CrossRefPubMed Tivol EA, Borriello F, Schweitzer AN et al (1995) Loss of CTLA-4 leads to massive lymphoproliferation and fatal multiorgan tissue destruction, revealing a critical negative regulatory role of CTLA-4. Immunity 3:541–547CrossRefPubMed
6.
go back to reference Waterhouse P et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988CrossRefPubMed Waterhouse P et al (1995) Lymphoproliferative disorders with early lethality in mice deficient in Ctla-4. Science 270:985–988CrossRefPubMed
8.
9.
go back to reference Ishida Y, Agata Y, Shibahara K et al (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895PubMedPubMedCentral Ishida Y, Agata Y, Shibahara K et al (1992) Induced expression of PD-1, a novel member of the immunoglobulin gene superfamily, upon programmed cell death. EMBO J 11:3887–3895PubMedPubMedCentral
10.
go back to reference Agata Y et al (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772CrossRefPubMed Agata Y et al (1996) Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes. Int Immunol 8:765–772CrossRefPubMed
11.
go back to reference Chikuma S et al (2009) PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol 182:6682–6689CrossRefPubMed Chikuma S et al (2009) PD-1-mediated suppression of IL-2 production induces CD8+ T cell anergy in vivo. J Immunol 182:6682–6689CrossRefPubMed
12.
go back to reference Nishimura H et al (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 8:773–780CrossRefPubMed Nishimura H et al (1996) Developmentally regulated expression of the PD-1 protein on the surface of double-negative (CD4-CD8-) thymocytes. Int Immunol 8:773–780CrossRefPubMed
13.
14.
go back to reference Freeman GJ et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034CrossRefPubMedPubMedCentral Freeman GJ et al (2000) Engagement of the PD-1 immunoinhibitory receptor by a novel B7 family member leads to negative regulation of lymphocyte activation. J Exp Med 192:1027–1034CrossRefPubMedPubMedCentral
15.
go back to reference Dong H, Zhu G, Tamada K et al (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369CrossRefPubMed Dong H, Zhu G, Tamada K et al (1999) B7-H1, a third member of the B7 family, co-stimulates T-cell proliferation and interleukin-10 secretion. Nat Med 5:1365–1369CrossRefPubMed
16.
go back to reference Latchman Y et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268CrossRefPubMed Latchman Y et al (2001) PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol 2:261–268CrossRefPubMed
18.
go back to reference Yamazaki T et al (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169:5538–5545CrossRefPubMed Yamazaki T et al (2002) Expression of programmed death 1 ligands by murine T cells and APC. J Immunol 169:5538–5545CrossRefPubMed
20.
go back to reference Romberg N et al (2013) Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival. J Allergy Clin Immunol 131:1691–1693CrossRefPubMedPubMedCentral Romberg N et al (2013) Gain-of-function STAT1 mutations are associated with PD-L1 overexpression and a defect in B-cell survival. J Allergy Clin Immunol 131:1691–1693CrossRefPubMedPubMedCentral
21.
go back to reference Liang SC et al (2003) Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 33:2706–2716CrossRefPubMed Liang SC et al (2003) Regulation of PD-1, PD-L1, and PD-L2 expression during normal and autoimmune responses. Eur J Immunol 33:2706–2716CrossRefPubMed
22.
go back to reference Lucas JA, Menke J, Rabacal WA et al (2008) Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 181:2513–2521CrossRefPubMedPubMedCentral Lucas JA, Menke J, Rabacal WA et al (2008) Programmed death ligand 1 regulates a critical checkpoint for autoimmune myocarditis and pneumonitis in MRL mice. J Immunol 181:2513–2521CrossRefPubMedPubMedCentral
23.
go back to reference Latchman YE et al (2004) PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA 101:10691–10696CrossRefPubMedPubMedCentral Latchman YE et al (2004) PD-L1-deficient mice show that PD-L1 on T cells, antigen-presenting cells, and host tissues negatively regulates T cells. Proc Natl Acad Sci USA 101:10691–10696CrossRefPubMedPubMedCentral
25.
go back to reference Nishimura H, Nose M, Hiai H et al (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151CrossRefPubMed Nishimura H, Nose M, Hiai H et al (1999) Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 11:141–151CrossRefPubMed
26.
go back to reference Nishimura H et al (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322CrossRefPubMed Nishimura H et al (2001) Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science 291:319–322CrossRefPubMed
27.
go back to reference Okazaki T et al (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9:1477–1483CrossRefPubMed Okazaki T et al (2003) Autoantibodies against cardiac troponin I are responsible for dilated cardiomyopathy in PD-1-deficient mice. Nat Med 9:1477–1483CrossRefPubMed
28.
go back to reference Wang J, Yoshida T, Nakaki F et al (2005) Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA 102:11823–11828CrossRefPubMedPubMedCentral Wang J, Yoshida T, Nakaki F et al (2005) Establishment of NOD-Pdcd1-/- mice as an efficient animal model of type I diabetes. Proc Natl Acad Sci USA 102:11823–11828CrossRefPubMedPubMedCentral
29.
go back to reference Wang J et al (2010) PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol 22:443–452CrossRefPubMed Wang J et al (2010) PD-1 deficiency results in the development of fatal myocarditis in MRL mice. Int Immunol 22:443–452CrossRefPubMed
30.
go back to reference Okazaki T, Maeda A, Nishimura H et al (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 98:13866–13871CrossRefPubMedPubMedCentral Okazaki T, Maeda A, Nishimura H et al (2001) PD-1 immunoreceptor inhibits B cell receptor-mediated signaling by recruiting src homology 2-domain-containing tyrosine phosphatase 2 to phosphotyrosine. Proc Natl Acad Sci USA 98:13866–13871CrossRefPubMedPubMedCentral
32.
go back to reference Yokosuka T, Takamatsu M, Kobayashi-Imanishi W et al (2012) Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 209:1201–1217CrossRefPubMedPubMedCentral Yokosuka T, Takamatsu M, Kobayashi-Imanishi W et al (2012) Programmed cell death 1 forms negative costimulatory microclusters that directly inhibit T cell receptor signaling by recruiting phosphatase SHP2. J Exp Med 209:1201–1217CrossRefPubMedPubMedCentral
35.
36.
go back to reference Rui Y, Honjo T, Chikuma S (2013) Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. Proc Natl Acad Sci USA 110:16073–16078CrossRefPubMedPubMedCentral Rui Y, Honjo T, Chikuma S (2013) Programmed cell death 1 inhibits inflammatory helper T-cell development through controlling the innate immune response. Proc Natl Acad Sci USA 110:16073–16078CrossRefPubMedPubMedCentral
38.
go back to reference Barber DL et al (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687CrossRefPubMed Barber DL et al (2006) Restoring function in exhausted CD8 T cells during chronic viral infection. Nature 439:682–687CrossRefPubMed
39.
go back to reference Horne-Debets JM et al (2013) PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep 5:1204–1213CrossRefPubMed Horne-Debets JM et al (2013) PD-1 dependent exhaustion of CD8+ T cells drives chronic malaria. Cell Rep 5:1204–1213CrossRefPubMed
40.
go back to reference Lazar-Molnar E et al (2010) Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci USA 107:13402–13407CrossRefPubMedPubMedCentral Lazar-Molnar E et al (2010) Programmed death-1 (PD-1)-deficient mice are extraordinarily sensitive to tuberculosis. Proc Natl Acad Sci USA 107:13402–13407CrossRefPubMedPubMedCentral
41.
go back to reference Barber DL, Mayer-Barber KD, Feng CG et al (2011) CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 186:1598–1607CrossRefPubMed Barber DL, Mayer-Barber KD, Feng CG et al (2011) CD4 T cells promote rather than control tuberculosis in the absence of PD-1-mediated inhibition. J Immunol 186:1598–1607CrossRefPubMed
42.
go back to reference Tousif S, Singh Y, Prasad DV et al (2011) T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection. PLoS One 6:e19864CrossRefPubMedPubMedCentral Tousif S, Singh Y, Prasad DV et al (2011) T cells from Programmed Death-1 deficient mice respond poorly to Mycobacterium tuberculosis infection. PLoS One 6:e19864CrossRefPubMedPubMedCentral
43.
go back to reference Odorizzi PM, Pauken KE, Paley MA et al (2015) Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J Exp Med 212:1125–1137CrossRefPubMedPubMedCentral Odorizzi PM, Pauken KE, Paley MA et al (2015) Genetic absence of PD-1 promotes accumulation of terminally differentiated exhausted CD8+ T cells. J Exp Med 212:1125–1137CrossRefPubMedPubMedCentral
44.
go back to reference Honda T, Egen JG, Lammermann T et al (2014) Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40:235–247CrossRefPubMedPubMedCentral Honda T, Egen JG, Lammermann T et al (2014) Tuning of antigen sensitivity by T cell receptor-dependent negative feedback controls T cell effector function in inflamed tissues. Immunity 40:235–247CrossRefPubMedPubMedCentral
45.
go back to reference Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736CrossRefPubMed Leach DR, Krummel MF, Allison JP (1996) Enhancement of antitumor immunity by CTLA-4 blockade. Science 271:1734–1736CrossRefPubMed
46.
go back to reference Thompson RH et al (2004) Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 101:17174–17179CrossRefPubMedPubMedCentral Thompson RH et al (2004) Costimulatory B7-H1 in renal cell carcinoma patients: indicator of tumor aggressiveness and potential therapeutic target. Proc Natl Acad Sci USA 101:17174–17179CrossRefPubMedPubMedCentral
47.
go back to reference Wu C, Zhu Y, Jiang J et al (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108:19–24CrossRefPubMed Wu C, Zhu Y, Jiang J et al (2006) Immunohistochemical localization of programmed death-1 ligand-1 (PD-L1) in gastric carcinoma and its clinical significance. Acta Histochem 108:19–24CrossRefPubMed
48.
go back to reference Nakanishi J, Wada Y, Matsumoto K et al (2007) Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56:1173–1182CrossRefPubMed Nakanishi J, Wada Y, Matsumoto K et al (2007) Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother 56:1173–1182CrossRefPubMed
49.
go back to reference Hamanishi J et al (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104:3360–3365CrossRefPubMedPubMedCentral Hamanishi J et al (2007) Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci USA 104:3360–3365CrossRefPubMedPubMedCentral
50.
go back to reference Hino R et al (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116:1757–1766CrossRefPubMed Hino R et al (2010) Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer 116:1757–1766CrossRefPubMed
51.
go back to reference Iwai Y, Ishida M, Tanaka Y et al (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99:12293–12297CrossRefPubMedPubMedCentral Iwai Y, Ishida M, Tanaka Y et al (2002) Involvement of PD-L1 on tumor cells in the escape from host immune system and tumor immunotherapy by PD-L1 blockade. Proc Natl Acad Sci USA 99:12293–12297CrossRefPubMedPubMedCentral
52.
go back to reference Curiel TJ et al (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567CrossRefPubMed Curiel TJ et al (2003) Blockade of B7-H1 improves myeloid dendritic cell-mediated antitumor immunity. Nat Med 9:562–567CrossRefPubMed
53.
go back to reference Brahmer JR et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175CrossRefPubMedPubMedCentral Brahmer JR et al (2010) Phase I study of single-agent anti-programmed death-1 (MDX-1106) in refractory solid tumors: safety, clinical activity, pharmacodynamics, and immunologic correlates. J Clin Oncol 28:3167–3175CrossRefPubMedPubMedCentral
56.
go back to reference Terawaki S et al (2011) IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 186:2772–2779CrossRefPubMed Terawaki S et al (2011) IFN-alpha directly promotes programmed cell death-1 transcription and limits the duration of T cell-mediated immunity. J Immunol 186:2772–2779CrossRefPubMed
57.
go back to reference Wolchok JD et al (2013) Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med 2013:2 Wolchok JD et al (2013) Nivolumab plus Ipilimumab in Advanced Melanoma. N Engl J Med 2013:2
58.
go back to reference Okazaki T, Chikuma S, Iwai Y et al (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14:1212–1218CrossRefPubMed Okazaki T, Chikuma S, Iwai Y et al (2013) A rheostat for immune responses: the unique properties of PD-1 and their advantages for clinical application. Nat Immunol 14:1212–1218CrossRefPubMed
60.
go back to reference Martin-Liberal J, Furness AJ, Joshi K et al (2015) Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother 64:765–767CrossRef Martin-Liberal J, Furness AJ, Joshi K et al (2015) Anti-programmed cell death-1 therapy and insulin-dependent diabetes: a case report. Cancer Immunol Immunother 64:765–767CrossRef
61.
go back to reference Loochtan AI, Nickolich MS, Hobson-Webb LD (2015) Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle Nerve 52:307–308CrossRefPubMed Loochtan AI, Nickolich MS, Hobson-Webb LD (2015) Myasthenia gravis associated with ipilimumab and nivolumab in the treatment of small cell lung cancer. Muscle Nerve 52:307–308CrossRefPubMed
Metadata
Title
Basics of PD-1 in self-tolerance, infection, and cancer immunity
Author
Shunsuke Chikuma
Publication date
01-06-2016
Publisher
Springer Japan
Published in
International Journal of Clinical Oncology / Issue 3/2016
Print ISSN: 1341-9625
Electronic ISSN: 1437-7772
DOI
https://doi.org/10.1007/s10147-016-0958-0

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