A mutational signature and significantly mutated driver genes associated with immune checkpoint inhibitor response across multiple cancers

Immune checkpoint inhibitor (ICI) treatments dramatically prolong the survival outcomes of several advanced cancers. However, as multiple studies reported, only a subset of patients could benefit from the ICI treatment. In this study, we aim to uncover novel molecular biomarkers predictive of immunotherapy efficacy across multiple cancers. Pre-treatment somatic mutational profiles and immunotherapy clinical information were obtained from 1097 samples of multiple cancers, including melanoma, non-small cell lung cancer (NSCLC), clear cell renal cell carcinoma (ccRCC), bladder carcinoma (BLCA), and head and neck squamous cell carcinoma (HNSCC). Muta-tional signatures, molecular subtypes, and significantly mutated genes (SMGs) were determined, and their connections with ICI response and outcome were also evaluated. We extracted a total of six mutational signatures across all samples. Among, a mutational signature featured by T > C substitutions was identified to associate with an ICI resistance. A molecular subtype determined based on mutational activities was connected with a significantly improved ICI response rate and outcome. Totaling 50 SMGs were identified, and we observed that patients with COL11A1 or COL4A6 mutations exhibited a superior ICI treatment efficacy than those without such mutations. In this study, we uncovered several novel molecular determinants of cancer immunotherapy response under a multiple-cancer setting, which provides clues for enrolling patients to receive immunotherapy and customizing personalized treatment strategies.

Automated summary

In this study, we identified new molecular biomarkers predictive of immunotherapy efficacy across multiple cancers. Mutational signatures, molecular subtypes, and significantly mutated genes (SMGs) were determined and their connections with ICI response and outcome were evaluated. We discovered that a mutational signature featuring T > C substitutions was associated with ICI resistance, and a molecular subtype based on mutational activities correlated with improved ICI response rate and outcome. Additionally, patients with COL11A1 or COL4A6 mutations exhibited superior ICI treatment efficacy.