Genomic mediators of acquired resistance to immunotherapy in metastatic melanoma

Highlights•Somatic mutations leading to immunotherapy resistance are poorly characterized•Resistance-associated genomic mutations in SEC24C/D were observed in patients•SEC24 mutations exhibited diminished STING signaling and innate immune signaling•SEC24-mutant cells exhibited lower antigen presentation and activation of T cellsSummaryAlthough 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 mutations observed in patients exhibit diminished STING signaling, including decreased type I interferon production, antigen presentation, and a reduced capacity to activate cytotoxic T cells. This study nominates a role for aberrant STING trafficking in acquired resistance to ICIs.Graphical abstract