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

1. J Hematol Oncol. 2024 Oct 14;17(1):97. doi: 10.1186/s13045-024-01618-6. NPM1 inhibits tumoral antigen presentation to promote immune evasion and tumor progression. Wang X(1), Chai Y(1), Quan Y(1), Wang J(1), Song J(1), Zhou W(1), Xu X(1), Xu H(2), Wang B(1), Cao X(3)(4). Author information: (1)Department of Immunology, Center for Immunotherapy, Institute of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China. (2)Frontier Research Center for Cell Response, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, 300071, China. (3)Department of Immunology, Center for Immunotherapy, Institute of Basic Medicine, Peking Union Medical College, Chinese Academy of Medical Sciences, Beijing, 100005, China. caoxt@immunol.org. (4)Frontier Research Center for Cell Response, Institute of Immunology, College of Life Sciences, Nankai University, Tianjin, 300071, China. caoxt@immunol.org. 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: High levels of NPM1 expression predict low survival rates in various human tumors. Loss of NPM1 inhibited tumor progression and enhanced the survival of tumor-bearing mice. Npm1-deficient tumors showed increased CD8+ 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. © 2024. The Author(s). DOI: 10.1186/s13045-024-01618-6 PMCID: PMC11479574 PMID: 39402629 [Indexed for MEDLINE] Conflict of interest statement: The authors declare no competing interests.