Common inherited loss-of-function mutations in the innate sensor NOD2 contribute to exceptional immune response to cancer immunotherapy.

ABSTRACT: Lung cancers and melanomas have many somatically mutated self-proteins that would be expected to trigger an immune rejection response, yet therapeutic responses can only be induced in a subset of patients. Here, we investigated the possibility that inherited differences in immune tolerance checkpoints contribute to variability in outcomes. Whole genome sequencing revealed biallelic germline loss-of-function (LOF) mutations in the immune tolerance checkpoint gene, NOD2, in an exceptional immune responder to targeted radiotherapy for metastatic melanoma. In 40 exceptional immune responders to anti-PD1 monotherapy for non-small cell lung cancer (NSCLC), genome sequencing showed 30% had inherited a NOD2 LOF variant, more than twice the population frequency (P = 0.0021). Co

SUBMITTER: Barnet MB 

PROVIDER: S-EPMC12280981 | biostudies-literature | 2025 Jul

REPOSITORIES: biostudies-literature