Exomics and immunogenics: Bridging mutational load and immune checkpoints efficacy

Abstract

Anti-PD-1/PD-L1 antibodies are emerging as promising anticancer therapeutics. Interestingly, elevated response rates to these agents are mostly documented among patients with tumors that bear high level of somatic mutations, like melanoma or non-small cell lung carcinoma. We herein formulate the hypothesis that high levels of mutational heterogeneity in the tumor could be the key for the success of immune checkpoint-targeting therapies.

Keywords: PD-1; PD-L1; immune checkpoints; immunotherapy; mutational heterogeneity.

Figure 1. Link between mutational heterogeneity and response to immune checkpoint blockers. (A) Mutational heterogeneity of tumors and overall response rates (ORRs) to PD-1/PD-L1-targeting agents. Colored bars indicate the median frequency of somatic mutations per megabase (Mb) reported for patients affected by different solid tumors. Yellow arrows represent the ORRs of these patients to anti-PD-1/PD-L1 antibodies, as detailed in Table 1. NSCLC, non-small cell lung carcinoma. (B) Correlation between median frequency of somatic mutations and ORR to PD-1/PD-L1-targeting agents in solid tumors. Dot size is proportional to the number of patients in which the efficacy of anti-PD-1/PD-L1 antibodies was tested. The red dashed line represents the LOESS regression curve. The P value is derived from a linear univariate model (median somatic mutation frequency ~ORR to anti-PD-1/PD-L1 agents).