• 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

MELANOMA

• 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

NSCLC

• 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

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%).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

RESISTANCE

• 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