Programmed death receptor-1 (PD-1), an immune checkpoint receptor, is overexpressed in cancer, leading to increased T-cell exhaustion and a diminished antitumor response. Blockade of PD-1 may restore cytotoxic T cells immune function.
In cancer, PD-L1 and PD-L2 are expressed on the surface of tumor cells, promoting T-cell exhaustion.1-3,6-8
This suggests a role for PD-L1 and PD-L2 in tumor immune evasion.9-12
Current data indicate that PD-L1 and PD-L2 are expressed in multiple solid tumors and hematologic malignancies, including renal cell cancer, melanoma, non-small cell lung cancer, esophageal cancer, pancreatic cancer, hepatocellular carcinoma, and lymphoma.8-13
In the tumor microenvironment, T-cell exhaustion begins when repeated exposure to tumor antigen steadily increases PD-1 activity: as uncontrolled PD-1 signaling multiplies, T cells begin to lose their ability to respond.3,6,7
Over time, exhausted T cells become increasingly disabled and lose essential functions such as the ability to reproduce, fight tumor cells, and finally, survive.14
Tumor-infiltrating T cells across solid tumors and hematologic malignancies often show evidence of exhaustion, including:
Upregulation of PD-1 and other inhibitors of immune function.3
Decreased production of cytokines, the cell-signaling molecules that help guide the immune response.3,15
Preclinical studies have shown that PD-1 blockade reinvigorates exhausted T cells and restores their cytotoxic immune function.16
Additionally, preclinical studies suggest that complete inhibition of PD-1 signaling through both PD-L1 and PD-L2 may be more effective at reversing T-cell exhaustion than through the inhibition of PD-L1 alone.17
Continuing research seeks to understand the impact of PD-1 pathway blockade on the reversal of T-cell exhaustion, and investigates the inhibition of PD-1 with other immune pathways.
Freeman GJ, Long AJ, Iwai Y, 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(7):1027-1034.
Latchman Y, Wood CR, Chernova T, et al. PD-L2 is a second ligand for PD-1 and inhibits T cell activation. Nat Immunol. 2001;2(3):261-268.
Ahmadzadeh M, Johnson LA, Heemskerk B, et al. Tumor antigen–specific CD8 T cells infiltrating the tumor express high levels of PD-1 and are functionally impaired. Blood. 2009;114(8):1537-1544.
Barber DL, Wherry EJ, Masopust D, et al. Restoring function in exhausted CD8 T cells during chronic viral infection. Nature. 2006;439(7077):682-687.
Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319-322.
Catakovic K, Klieser E, Neureiter D, Geisberger R. T cell exhaustion: from pathophysiological basics to tumor immunotherapy. Cell Commun Signal. 2017;15(1):1. doi:10.1186/s12964-016-0160-z.
Peng W, Liu C, Xu C, et al. PD-1 blockade enhances T-cell migration to tumors by elevating IFN-γ inducible chemokines. Cancer Res. 2012;72(20):5209-5218.
Taube JM, Klein A, Brahmer JR, et al. Association of PD-1, PD-1 ligands, and other features of the tumor immune microenvironment with response to anti–PD-1 therapy. Clin Cancer Res. 2014;20(19):5064-5074.
Nomi T, Sho M, Akahori T, et al. Clinical significance and therapeutic potential of the programmed death-1 ligand/programmed death-1 pathway in human pancreatic cancer. Clin Cancer Res. 2007;13(7):2151-2157.
Ohigashi Y, Sho M, Yamada Y, et al. Clinical significance of programmed death-1 ligand-1 and programmed death-1 ligand-2 expression in human esophageal cancer. Clin Cancer Res. 2005;11(8):2947-2953.
Hamanishi J, Mandai M, Iwasaki M, et al. Programmed cell death 1 ligand 1 and tumor-infiltrating CD8+ T lymphocytes are prognostic factors of human ovarian cancer. Proc Natl Acad Sci U S A. 2007;104(9):3360-3365.
Green MR, Monti S, Rodig SJ, et al. Integrative analysis reveals selective 9p24.1 amplification, increased PD-1 ligand expression, and further induction via JAK2 in nodular sclerosing Hodgkin lymphoma and primary mediastinal large B-cell lymphoma. Blood. 2010;116(17):3268-3377.
Jung HI, Jeong D, Ji S, et al. Overexpression of PD-L1 and PD-L2 is associated with poor prognosis in patients with hepatocellular carcinoma. Cancer Res Treat. 2017;49(1):246-254.
Lee J, Ahn E, Kissick HT, Ahmed R. Reinvigorating exhausted T cells by blockade of the PD-1 pathway. For Immunopathol Dis Therap. 2015;6(1-2):7-17.
Zhang L, Gajewski TF, Kline J. PD-1/PD-L1 interactions inhibit antitumor immune responses in a murine acute myeloid leukemia model. Blood. 2009;114(8):1545-1552.
Sznol M, Chen L. Antagonist antibodies to PD-1 and B7-H1 (PD-L1) in the treatment of advanced human cancer. Clin Cancer Res. 2013;19(5):1021-1034.
Hobo W, Maas F, Adisty N, et al. siRNA silencing of PD-L1 and PD-L2 on dendritic cells augments expansion and function of minor histocompatibility antigen–specific CD8+ T cells. Blood. 2010;116(22):4501-4511.
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