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.5,6,20
    • Prolonged TCR stimulation during an ongoing immune response can cause upregulated PD-1 expression.20
    • 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, thus down-regulating the immune response.20


  • 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 and patients with tumors that contain a high density of tumor-infiltrating lymphocytes (TILs) are most likely to respond to immunotherapy, although 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:8,18,23,29
    • 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 copy number amplification of the genes PD-L1 and JAK2 can result in high expression of PD-L1 protein and poor prognosis; however, actual response to PD-1/PD-L1 antagonistic inhibition does not necessarily follow this biomarker pattern.18,23


  • Patients with melanoma have shown around 40-50% ORR to PD-1/PD-L1 antagonism irrespective of PD-L1 protein expression.23
  • For melanoma, the promises that PD-L1 expression in tumor samples could serve as a predictive marker have been disappointing.24
  • Instead, melanoma response to anti-PD-1 therapy correlates more with mutational load, which tends to be high in melanoma.24,25


  • Anti-PD-1/PD-L1 therapies for NSCLC tend to use PD-L1 protein expression to select patients as response rates are higher in PD-L1-expressing tumors relative to unselected populations.23,26
  • 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 associated with the smoking population.26
  • Randomized phase III 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.18,30


  • 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%).23
  • In HNSCC, smoking seems to contribute to a more immunosuppressive tumor microenvironment (TME) and negatively impact anti-PD-1/PD-L1 efficacy.31
  • Increased TMB and neoantigen load have been shown to correlate with response to anti-PD-1/PD-L1 therapies in HPV- HNSCC, whereas most of the studies conducted to date have refuted their predictive value in HPV+ patients.31


  • Up to 60% of patients across different tumor types display primary resistance to anti-PD-1/PD-L1 agents.31
  • 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.31
  • To overcome the resistance, many ongoing clinical trials are evaluating combination strategies with other immunotherapies, targeted agents, chemotherapy and radiotherapy.31
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  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.
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  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.
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  20. 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.
  21. Garces AHI, et al. Building on the anti-PD1/PD-L1 backbone: combination immunotherapy for cancer. Expert Opinion on Investigational Drugs. 2019;28(8):695-708.
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