| Summary: | Efficient predictive biomarkers are urgently needed to identify non-small cell lung cancer (NSCLC) patients who could benefit from immune checkpoint blockade (ICB) therapy. Since chromatin remodeling is required for DNA repair process, we asked whether mutations in chromatin remodeling genes could increase tumor mutational burden (TMB) and predict response to ICB therapy in NSCLC. Analysis of seven ICB-treated NSCLC cohorts revealed that mutations of three chromatin remodeling-related genes, including <i>KMT2C</i>, <i>BCOR</i> and <i>KDM5C</i>, were significantly associated with ICB response, and combined mutations of these three genes further enhance this association. NSCLC patients with <i>KMT2C/BCOR/KDM5C</i> mutations had comparable clinical outcomes to TMB-high patients in terms of objective response rate, durable clinical benefit and overall survival. Although <i>KMT2C/BCOR/KDM5C</i> mutations were positively correlated with TMB levels in NSCLC, the association of this mutation with better ICB response was independent of tumor TMB and programmed death-ligand 1 (PD-L1) level, and combination of <i>KMT2C/BCOR/KDM5C</i> mutations with TMB or PD-L1 further improve the prediction of ICB response in NSCLC patients. Cancer Genome Atlas (TCGA) pan-cancer analysis suggested that the association of <i>KMT2C/BCOR/KDM5C</i> mutations with ICB response observed here might not result from DNA repair defects. In conclusion, our data indicate that <i>KMT2C/BCOR/KDM5C</i> mutation has the potential to serve as a predictive biomarker, alone or combined with PD-L1 expression or TMB, for ICB therapy in NSCLC.
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