Mutated processes predict immune checkpoint inhibitor therapy benefit in metastatic melanoma

Immune Checkpoint Inhibitor (ICI) therapy has revolutionized treatment for advanced melanoma; however, only a subset of patients benefit from this treatment. Despite considerable efforts, the Tumor Mutation Burden (TMB) is the only FDA-approved biomarker in melanoma. However, the mechanisms underlying TMB association with prolonged ICI survival are not entirely understood and may depend on numerous confounding factors. To identify more interpretable ICI response biomarkers based on tumor mutations, we train classifiers using mutations within distinct biological processes. We evaluate a variety of feature selection and classification methods and identify key mutated biological processes that provide improved predictive capability compared to the TMB. The top mutated processes we identify are leukocyte and T-cell proliferation regulation, which demonstrate stable predictive performance across different data cohorts of melanoma patients treated with ICI. This study provides biologically interpretable genomic predictors of ICI response with substantially improved predictive performance over the TMB. Tumour mutational burden is a biomarker of immune checkpoint inhibitor response, but their association is not fully understood. Here, the authors train classifiers to identify key mutated processes which show stable predictive performance in multiple melanoma cohorts.

Automated summary

This study identifies key mutated processes associated with immune checkpoint inhibitor response in melanoma patients, demonstrating improved predictive capability compared to tumor mutational burden.