PD-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.5,6,13
    • Prolonged TCR stimulation during an ongoing immune response can cause upregulated PD-1 expression.13
    • Tumor cells can express PD-L1 (and PD-L2, not shown) as a consequence of inflammatory cytokines and/or oncogenic signaling pathways. PD-1:PD-L1 binding inhibits TCR-mediated positive signaling, leading to reduced proliferation, reduced cytokine secretion, and reduced survival; this results in a downregulation of the immune response.13

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
  • Effective cancer immunotherapy depends on the status of the immune response in the tumor microenvironment. Patients with tumors that contain a high density of tumor-infiltrating lymphocytes (TILs) are most likely to respond to immunotherapy; however, this is not sufficient for complete cancer eradication.
  • 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 general, improved response to PD1/PD-L1 inhibitors tends to correlate with patient tumors having:8,12,14,16
    • Higher PD-L1 protein expression
    • Higher mutational load or tumor mutational burden (TMB)
    • Higher mismatch repair deficiency (MMR) and microsatellite instability (MSI)
    • Earlier line of therapy
  • Many kinds of genomic aberrations, such as the copy number amplification of the genes¬†PD-L1¬†and¬†JAK2¬†can result in high expression of PD-L1 protein and poor prognosis; however, the actual response to PD-1/PD-L1 antagonistic inhibition does not necessarily follow this biomarker pattern.12,14

Non-small cell lung cancer(NSCLC)

  • Anti-PD-1/PD-L1 therapies for NSCLC tend to use PD-L1 protein expression to select patients because response rates are higher in PD-L1-expressing tumors relative to unselected populations.14,15
  • In general, PD-1/PD-L1-inhibiting therapies show more benefit in smokers versus non-smokers; however, evidence suggests that the higher ORR is likely due to the higher tumor mutational burden (TMB) associated with the smoking population.15
  • Randomized phase 3 trials have indicated that patients carrying¬†EGFR¬†or¬†ALK¬†mutations exhibit less efficacy of anti-PD-1/PD-L1 treatment than those with wild-type, whereas¬†KRAS¬†mutations are likely to be predictors of favorable outcomes.12,17

Head and neck squamous cell carcinoma (HNSCC)

  • A statistically significant increase in ORR was observed in patients with HNSCC treated with a PD-1 inhibitor in PD-L1-positive (22%) versus PD-L1-negative (4%) tumors.14
  • In HNSCC, smoking seems to contribute to a more immunosuppressive tumor microenvironment (TME) and negatively impact anti-PD-1/PD-L1 efficacy.18
  • Increased TMB and neoantigen load have been shown to correlate with response to anti-PD-1/PD-L1 therapies in HPV-¬†HNSCC; however, most of the studies conducted to date have refuted their predictive value in HPV+¬†patients.18

RESISTANCE

  • Up to 60% of patients across different tumor types display primary resistance to anti-PD-1/PD-L1 agents.18
  • Several mechanisms have been suggested such as poor tumor immunogenicity, limited intratumoral immune cell infiltration, coexpression of multiple inhibitory receptors, and induction of immunosuppressive pathways within the TME.18
  • To overcome resistance, many ongoing clinical trials are evaluating combination strategies with other immunotherapies, targeted agents, chemotherapy and radiotherapy.18
  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. Yi M, Jiao D, Xu H, et al. Biomarkers for predicting efficacy of PD-1/PD-L1 inhibitors. Mol Cancer. 2018;17(1):129.
  13. Buchbinder EI, Desai A. CTLA-4 and PD-1 Pathways: Similarities, Differences, and Implications of Their Inhibition. Am J Clin Oncol. 2016;39(1):98-106.
  14. Chen Q, et al.  Drug response to PD-1/PD-L1 blockade: based on biomarkers. OncoTargets Ther.  2018;11:4673-4683.
  15. Califano R, et al.  Patient selection for anti-PD-1/PD-L1 therapy in advanced non-small-cell lung cancer: implications for clinical practice. Future Oncol. 2018;14(23):2415-2431.
  16. Gong J, et al. Development of PD-1 and PD-L1 inhibitors as a form of cancer immunotherapy: a comprehensive review of registration trial and future considerations. J Immunother Cancer. 2018;6:8.
  17. Miura Y, N Sunaga. Role of Immunotherapy for Oncogene-Driven Non-Small Cell Lung Cancer. Cancers.  2018;10:245.
  18. Oliva M, et al. Immune biomarkers of response to immunecheckpoint inhibitors in head and neck squamous cell carcinoma. Ann Oncol. 2019;30:57‚Äď67.