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Blockade of the PD-1 pathway diagram

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 activity1,2
  • 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 autoimmunity3-5

Diagram of how upregulation of PD-1 can potentially cause T-cell exhaustion

  • Preclinical studies have shown that PD-1 blockade reinvigorates exhausted T cells and restores their cytotoxic immune function16
    • 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 alone17
  • 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
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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.