Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma.

ABSTRACT: Although some patients with metastatic melanoma experience durable responses to immune checkpoint inhibitors (ICIs), most exhibit intrinsic or acquired resistance to these therapies. Here, we compare somatic genomic profiles from matched pre-treatment and post-resistance tumor biopsies in patients (n = 25) with metastatic melanoma who exhibited heterogeneous ICI responses to nominate additional mediators of acquired resistance. We find that several acquired resistance tumors exhibit defects in B2M or JAK1/2, consistent with prior findings. We also discover resistance-associated mutations in SEC24C and SEC24D in 3 patients. SEC24 has an essential role in the trafficking of the dsDNA sensor STING and has been linked to interferonopathies. Melanoma cells engineered to express the SEC24C mutat

SUBMITTER: Schiantarelli J 

PROVIDER: S-EPMC12232206 | biostudies-literature | 2025 Feb

REPOSITORIES: biostudies-literature