The Programmed Death-1 Immune-suppressive Pathway: Barrier to Antitumor Immunity

Overview

Journal J Immunol

Specialty Allergy & Immunology

Date 2014 Oct 5

PMID 25281753

Citations 120

Authors

Suzanne Ostrand-Rosenberg

Lucas A Horn

Samuel T Haile

Affiliations

Soon will be listed here.

Abstract

Programmed death ligand 1 (PD-L1, also known as B7 homolog 1 or CD274) is a major obstacle to antitumor immunity because it tolerizes/anergizes tumor-reactive T cells by binding to its receptor programmed death-1 (CD279), renders tumor cells resistant to CD8(+) T cell- and FasL-mediated lysis, and tolerizes T cells by reverse signaling through T cell-expressed CD80. PD-L1 is abundant in the tumor microenvironment, where it is expressed by many malignant cells, as well as by immune cells and vascular endothelial cells. The critical role of PD-L1 in obstructing antitumor immunity has been demonstrated in multiple animal models and in recent clinical trials. This article reviews the mechanisms by which PD-L1 impairs antitumor immunity and discusses established and experimental strategies for maintaining T cell activation in the presence of PD-L1-expressing cells in the tumor microenvironment.

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References

Yi T, Li X, Yao S, Wang L, Chen Y, Zhao D . Host APCs augment in vivo expansion of donor natural regulatory T cells via B7H1/B7.1 in allogeneic recipients. J Immunol. 2011; 186(5):2739-49. PMC: 3786569. DOI: 10.4049/jimmunol.1002939. View

Taube J, Anders R, Young G, Xu H, Sharma R, McMiller T . Colocalization of inflammatory response with B7-h1 expression in human melanocytic lesions supports an adaptive resistance mechanism of immune escape. Sci Transl Med. 2012; 4(127):127ra37. PMC: 3568523. DOI: 10.1126/scitranslmed.3003689. View

Okazaki T, Maeda A, Nishimura H, Kurosaki T, Honjo T . 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 U S A. 2001; 98(24):13866-71. PMC: 61133. DOI: 10.1073/pnas.231486598. View

Lipson E, Vincent J, Loyo M, Kagohara L, Luber B, Wang H . PD-L1 expression in the Merkel cell carcinoma microenvironment: association with inflammation, Merkel cell polyomavirus and overall survival. Cancer Immunol Res. 2014; 1(1):54-63. PMC: 3885978. DOI: 10.1158/2326-6066.CIR-13-0034. View

Marzec M, Zhang Q, Goradia A, Raghunath P, Liu X, Paessler M . Oncogenic kinase NPM/ALK induces through STAT3 expression of immunosuppressive protein CD274 (PD-L1, B7-H1). Proc Natl Acad Sci U S A. 2008; 105(52):20852-7. PMC: 2634900. DOI: 10.1073/pnas.0810958105. View

Peach R, Bajorath J, Naemura J, Leytze G, Greene J, Aruffo A . Both extracellular immunoglobin-like domains of CD80 contain residues critical for binding T cell surface receptors CTLA-4 and CD28. J Biol Chem. 1995; 270(36):21181-7. DOI: 10.1074/jbc.270.36.21181. View

Patsoukis N, Sari D, Boussiotis V . PD-1 inhibits T cell proliferation by upregulating p27 and p15 and suppressing Cdc25A. Cell Cycle. 2012; 11(23):4305-9. PMC: 3552912. DOI: 10.4161/cc.22135. View

Amarnath S, Mangus C, Wang J, Wei F, He A, Kapoor V . The PDL1-PD1 axis converts human TH1 cells into regulatory T cells. Sci Transl Med. 2011; 3(111):111ra120. PMC: 3235958. DOI: 10.1126/scitranslmed.3003130. View

Shinohara T, Taniwaki M, Ishida Y, Kawaichi M, Honjo T . Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics. 1994; 23(3):704-6. DOI: 10.1006/geno.1994.1562. View

10.

Nakanishi J, Wada Y, Matsumoto K, Azuma M, Kikuchi K, Ueda S . Overexpression of B7-H1 (PD-L1) significantly associates with tumor grade and postoperative prognosis in human urothelial cancers. Cancer Immunol Immunother. 2006; 56(8):1173-82. PMC: 11029839. DOI: 10.1007/s00262-006-0266-z. View

11.

Gao Q, Wang X, Qiu S, Yamato I, Sho M, Nakajima Y . Overexpression of PD-L1 significantly associates with tumor aggressiveness and postoperative recurrence in human hepatocellular carcinoma. Clin Cancer Res. 2009; 15(3):971-9. DOI: 10.1158/1078-0432.CCR-08-1608. View

12.

Brahmer J, Tykodi S, Chow L, Hwu W, Topalian S, Hwu P . Safety and activity of anti-PD-L1 antibody in patients with advanced cancer. N Engl J Med. 2012; 366(26):2455-65. PMC: 3563263. DOI: 10.1056/NEJMoa1200694. View

13.

Iwai Y, Terawaki S, Honjo T . PD-1 blockade inhibits hematogenous spread of poorly immunogenic tumor cells by enhanced recruitment of effector T cells. Int Immunol. 2004; 17(2):133-44. DOI: 10.1093/intimm/dxh194. View

14.

Blank C, Brown I, Peterson A, Spiotto M, Iwai Y, Honjo T . PD-L1/B7H-1 inhibits the effector phase of tumor rejection by T cell receptor (TCR) transgenic CD8+ T cells. Cancer Res. 2004; 64(3):1140-5. DOI: 10.1158/0008-5472.can-03-3259. View

15.

Brown J, Dorfman D, Ma F, Sullivan E, Munoz O, Wood C . Blockade of programmed death-1 ligands on dendritic cells enhances T cell activation and cytokine production. J Immunol. 2003; 170(3):1257-66. DOI: 10.4049/jimmunol.170.3.1257. View

16.

Saudemont A, Jouy N, Hetuin D, Quesnel B . NK cells that are activated by CXCL10 can kill dormant tumor cells that resist CTL-mediated lysis and can express B7-H1 that stimulates T cells. Blood. 2004; 105(6):2428-35. DOI: 10.1182/blood-2004-09-3458. View

17.

Karwacz K, Bricogne C, Macdonald D, Arce F, Bennett C, Collins M . PD-L1 co-stimulation contributes to ligand-induced T cell receptor down-modulation on CD8+ T cells. EMBO Mol Med. 2011; 3(10):581-92. PMC: 3191120. DOI: 10.1002/emmm.201100165. View

18.

Duraiswamy J, Freeman G, 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(23):6900-12. PMC: 3851914. DOI: 10.1158/0008-5472.CAN-13-1550. View

19.

Lipson E, Sharfman W, Drake C, Wollner I, Taube J, Anders R . Durable cancer regression off-treatment and effective reinduction therapy with an anti-PD-1 antibody. Clin Cancer Res. 2012; 19(2):462-8. PMC: 3548952. DOI: 10.1158/1078-0432.CCR-12-2625. View

20.

Haile S, Bosch J, Agu N, Zeender A, Somasundaram P, Srivastava M . Tumor cell programmed death ligand 1-mediated T cell suppression is overcome by coexpression of CD80. J Immunol. 2011; 186(12):6822-9. PMC: 3377446. DOI: 10.4049/jimmunol.1003682. View