Genetic biomarkers for PD-1/PD-L1 blockade therapy

Immune checkpoint blockade therapy using antibodies against programmed cell death 1 (PD-1) and PD-1 ligand 1 (PD-L1) is revolutionizing cancer treatment (1-3). These antibodies provide long-term durable responses for patients with various types of advanced cancers, such as melanoma, non–small-cell lung cancer, kidney cancer, and Hodgkin lymphoma (1-3). Accumulating evidence suggests that these agents convey their therapeutic effects through targeting the PD-1/PD-L1 immune checkpoint to unleash anti-tumor immune responses. In turn, it is supposed that cancer cells depend critically on evading immune surveillance for their malignant growth. As immune checkpoint blockade therapy has benefited only a subset of patients, defining biomarkers that can predict therapeutic efficacy and adverse effects is of urgent importance, which is substantiated by recent approvals for PD-L1 diagnostic tests (2). Here we provide a brief overview of the recent development of genetic biomarkers for PD-1/PD-L1 blockade therapies, with special focus on PD-L1 genetic abnormalities, including its 3′-UTR disruption. Early studies demonstrated the potential value of immunological biomarkers, such as intratumoral lymphoid infiltrates and PD-L1 expression on tumor or infiltrating immune cells, for predicting response to PD-1/PD-L1 blockade (1, 2). However, subsequent studies have revealed a lower but significant response rate in patients with PD-L1-tumors, raising questions about the utility of these immunological markers as an ideal selection criterion for PD-1/PD-L1 blockade therapy (2). Indeed, estimated from the results across 15 studies including various solid cancer types, the overall response rate to PD-1/PD-L1 blockade was 48% in patients with PD-L1 + tumors, in contrast to 15% in those with PD-L1-tumors. In addition, especially in clinical setting, accurate measurement and scoring of PD-L1 protein expression are hampered by a variety of technical and biological pitfalls (2). Genomics-based approaches have the potential to complement immunological biomarkers. In particular, Rizvi et al. demonstrated that a higher load of nonsynonymous mutations and neoantigens detected by whole-exome sequencing positively correlated with clinical response to an anti-PD-1 antibody (pembrolizumab) in non-small cell lung cancer (NSCLC) patients. Moreover, candidate neoantigens were experimentally validated using a high-throughput multimer screening to identify neoantigen-specific T cells. In one responder, neoantigen-specific T-cell reactivity paralleled tumor regression (4). In addition to neoantigen load, the extent of neoantigen intratumoral heterogeneity (ITH) within single tumors affects the sensitivity to immune modulation. An integrated analysis of ITH and neoantigen burden showed that the response to PD-1 blockade in patients with NSCLC was enhanced in tumors enriched for clonal neoantigens, i.e., those shared …