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PD-1

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.        
  • Programmed death receptor-1 (PD-1) is an immune checkpoint receptor on cytotoxic T cells. PD-1 has 2 ligands, programmed death ligand 1 (PD-L1) and programmed death ligand 2 (PD-L2).1-3
    • These ligands have overlapping functions in the ability to inhibit T-cell activity.1,2
  • Upregulation of PD-1, and PD-L1 and/or PD-L2 plays a key role in T-cell exhaustion and is an important factor in preventing autoimmunity.3-5
  • 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
    • Impaired ability to kill tumor cells.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.

View areas of research related to PD-1

Bladder Breast Esophageal, Gastroesophageal Gastric Glioblastoma Head & Neck Hematologic Malignancies Hepatocellular Carcinoma Lung Cancer Lymphoma Melanoma Multiple Myeloma Prostate Renal Cell Carcinoma Solid Tumors (General)

References

  1. 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.
  2. 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.
  3. 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.
  4. 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.
  5. Nishimura H, Okazaki T, Tanaka Y, et al. Autoimmune dilated cardiomyopathy in PD-1 receptor-deficient mice. Science. 2001;291(5502):319-322.
  6. 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.
  7. 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.
  8. 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.
  9. 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.
  10. 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.
  11. 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.
  12. 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.
  13. 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.
  14. 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.
  15. 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.
  16. 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.
  17. 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.