PD-1 (Programmed Death Protein 1)

Overview

  • Programmed death protein 1 (PD-1) is a type 1 cell surface receptor expressed by activated CD4+ and CD8+ T cells, natural killer (NK) T cells, and antigen-presenting cells (APCs).1,2
  • The PD-1 receptor has two ligands, programmed death ligand-1 (PD-L1) and programmed death ligand-2 (PD-L2), which are mainly expressed on APCs. Receptor/ligand interactions maintain immune homeostasis by reducing T-cell priming and inhibiting effector T-cell proliferation and function while increasing immunosuppressive regulatory T cell (Treg) function.1,3,4
  • T-cell activation by APCs via stimulation of the T-cell receptor (TCR) by major histocompatibility complexes (MHCs), costimulated by CD28 interactions with CD80 or CD86, upregulates the expression of PD-1 on those T cells.5,6
    • When PD-1 interacts with PD-L1 or PD-L2, PD-1 inactivates CD28 costimulatory and TCR-mediated signaling, thus down-regulating the immune response.5,6

Implications in cancer

  • Appropriation of the PD-L1/PD-1 pathway can be one mechanism by which the tumor evades immunosurveillance.7
    • Induction of PD-L1 expression on tumor cells, tumor-infiltrating APCs, and/or immune cells within the tumor microenvironment leads to suppression of immune responses and poor anti-tumor responses, permitting cancer progression and metastasis.8,9
    • Immunohistochemistry (IHC) has also detected PD-L1 expression in infiltrating lymphocytes in a variety of tumors.10
  • Evidence of T-cell exhaustion has been observed in T cells infiltrating many solid tumors.11
    • Chronic exposure to tumor antigen steadily increases the expression level of PD-1.11
    • Persistent expression of PD-1 on T cells induces T-cell exhaustion and loss of effector functions, such as proliferation, cytotoxicity, and survival.1
  • PD-L1 protein is commonly overexpressed in solid tumors.10
    • In NSCLC, up to 75% of tumor cells and up to 50% of infiltrating immune cells express PD-L1.12,13 Higher PD-L1 protein expression is found more frequently in females, never/former smokers, and those with adenocarcinomas. High cell-surface PD-L1 expression is also associated with the presence of activating EGFR mutations and ALK translocations.9,14
    • PD-L1 expression has been detected in up to 60% of melanomas, where it independently predicts for poorer prognosis.15,16
    • PD-L1 expression has been detected in up to 70% of epithelial ovarian cancers and is associated with decreased survival.17
  • Efficacy in patients with a lack of PD-L1 expression in the tumor suggests a role for anti—PD-1 therapy outside of the tumor microenvironment, consistent with PD-1 activity in the maintenance of immune homeostasis.18,19
  • The number of tumor types for which the PD-1/PD-L1 pathway is emerging as a potential therapeutic target is rapidly growing.
  1. Ohaegbulam KC, Assal A, Lazar-Molnar E, Yao Y, Zang X. Human cancer immunotherapy with antibodies to the PD-1 and PD-L1 pathway. Trends Mol Med. 2015;21(1):24-33.
  2. Gao J, Bernatchez C, Sharma P, Radvanyi LG, Hwu P. Advances in the development of cancer immunotherapies. Trends Immunol. 2013;34(2):90-98.
  3. 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.
  4. 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.
  5. Hui E, Cheung J, Zhu J, et al. T cell costimulatory receptor CD28 is a primary target for PD-1-mediated inhibition. Science. 2017;355(6332):1428-1433.
  6. O'Donnell JS, Smyth MJ, Teng MWL. PD1 functions by inhibiting CD28-mediated co-stimulation. Clin Transl Immunology. 2017;6(5):e138.
  7. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674.
  8. O'Donnell JS, Long GV, Scolyer RA, Teng MW, Smyth MJ. Resistance to PD1/PDL1 checkpoint inhibition. Cancer Treat Rev. 2017;52:71-81.
  9. D'Incecco A, Andreozzi M, Ludovini V, et al. PD-1 and PD-L1 expression in molecularly selected non-small-cell lung cancer patients. Br J Cancer. 2015;112(1):95-102.
  10. Kythreotou A, Siddique A, Mauri FA, Bower M, Pinato DJ. PD-L1. J Clin Pathol. 2018;71(3):189-194.
  11. 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.
  12. Scheel AH, Ansén S, Schultheis AM, et al. PD-L1 expression in non-small cell lung cancer: Correlations with genetic alterations. Oncoimmunology. 2016;5(5):e1131379.
  13. Sheng J, Fang W, Yu J, et al. Expression of programmed death ligand-1 on tumor cells varies pre and post chemotherapy in non-small cell lung cancer. Sci Rep. 2016;6:20090.
  14. Azuma K, Ota K, Kawahara A, et al. Association of PD-L1 overexpression with activating EGFR mutations in surgically resected nonsmall-cell lung cancer. Ann Oncol. 2014;25(10):1935-1940.
  15. Kaunitz GJ, Cottrell TR, Lilo M, et al. Melanoma subtypes demonstrate distinct PD-L1 expression profiles. Lab Invest. 2017;97(9):1063-1071.
  16. Hino R, Kabashima K, Kato Y, et al. Tumor cell expression of programmed cell death-1 ligand 1 is a prognostic factor for malignant melanoma. Cancer. 2010;116(7):1757-1766.
  17. 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.
  18. Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer. 2018;17(1):129.
  19. Sharma P, Callahan MK, Bono P, et al. Nivolumab monotherapy in recurrent metastatic urothelial carcinoma (CheckMate 032): a multicentre, open-label, two-stage, multi-arm, phase 1/2 trial. Lancet Oncol. 2016;17(11):1590-1598.

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