Integrated genomic analysis identifies a genetic mutation model predicting response to immune checkpoint inhibitors in melanoma

Abstract

Several biomarkers such as tumor mutation burden (TMB), neoantigen load (NAL), programmed cell-death receptor 1 ligand (PD-L1) expression, and lactate dehydrogenase (LDH) have been developed for predicting response to immune checkpoint inhibitors (ICIs) in melanoma. However, some limitations including the undefined cut-off value, poor uniformity of test platform, and weak reliability of prediction have restricted the broad application in clinical practice. In order to identify a clinically actionable biomarker and explore an effective strategy for prediction, we developed a genetic mutation model named as immunotherapy score (ITS) for predicting response to ICIs therapy in melanoma, based on whole-exome sequencing data from previous studies. We observed that patients with high ITS had better durable clinical benefit and survival outcomes than patients with low ITS in three independent cohorts, as well as in the meta-cohort. Notably, the prediction capability of ITS was more robust than that of TMB. Remarkably, ITS was not only an independent predictor of ICIs therapy, but also combined with TMB or LDH to better predict response to ICIs than any single biomarker. Moreover, patients with high ITS harbored the immunotherapy-sensitive characteristics including high TMB and NAL, ultraviolet light damage, impaired DNA damage repair pathway, arrested cell cycle signaling, and frequent mutations in NF1 and SERPINB3/4. Overall, these findings deserve prospective investigation in the future and may help guide clinical decisions on ICIs therapy for patients with melanoma.