Loss of Optineurin Drives Cancer Immune Evasion via Palmitoylation-Dependent IFNGR1 Lysosomal Sorting and Degradation.

ABSTRACT: Mutations in IFN and MHC signaling genes endow immunotherapy resistance. Patients with colorectal cancer infrequently exhibit IFN and MHC signaling gene mutations and are generally resistant to immunotherapy. In exploring the integrity of IFN and MHC signaling in colorectal cancer, we found that optineurin was a shared node between the two pathways and predicted colorectal cancer patient outcome. Loss of optineurin occurs in early-stage human colorectal cancer. Immunologically, optineurin deficiency was shown to attenuate IFNGR1 and MHC-I expression, impair T-cell immunity, and diminish immunotherapy efficacy in murine cancer models and patients with cancer. Mechanistically, we observed that IFNGR1 was S-palmitoylated on Cys122, and AP3D1 bound with and sorted palmitoylated IFNGR1 t

SUBMITTER: Du W 

PROVIDER: S-EPMC8292167 | biostudies-literature | 2021 Jul

REPOSITORIES: biostudies-literature