Work

NPM1 inhibits tumoral antigen presentation to promote immune evasion and tumor progression

Year: 2024

Type: article

Abstract: BACKGROUND: Tumor cells develop multiple mechanisms to facilitate their immune evasion. Identifying tumor-intrinsic factors that support immune evasion may provide new strategies for cancer immunotherapy. We aimed to explore the function and the mechanism of the tumor-intrinsic factor NPM1, a multifunctional nucleolar phosphoprotein, in cancer immune evasion and progression. METHODS: The roles of NPM1 in tumor progression and tumor microenvironment (TME) reprogramming were examined by subcutaneous inoculation of Npm1-deficient tumor cells into syngeneic mice, and then explored by CyTOF, flow cytometry, immunohistochemistry staining, and RNA-seq. The in-vitro T-cell killing of OVA-presenting tumor cells by OT-1 transgenic T cells was observed. The interaction of NPM1 and IRF1 was verified by Co-IP. The regulation of NPM1 in IRF1 DNA binding to Nlrc5, Ciita promoter was determined by dual-luciferase reporter assay and ChIP-qPCR. RESULTS: T cell infiltration and activation alongside the reduced presence of immunosuppressive cells. Npm1 deficiency increased MHC-I and MHC-II molecules and specific T-cell killing. Mechanistically, NPM1 associates with the transcription factor IRF1 and then sequesters IRF1 from binding to the Nlrc5 and Ciita promoters to suppress IRF1-mediated expression of MHC-I and MHC-II molecules in tumor cells. CONCLUSIONS: Tumor-intrinsic NPM1 promotes tumor immune evasion via suppressing IRF1-mediated antigen presentation to impair tumor immunogenicity and reprogram the immunosuppressive TME. Our study identifies NPM1 as a potential target for improving cancer immunotherapy.

Source: Journal of Hematology & Oncology

DOI: 10.1186/s13045-024-01618-6