Journal Article

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

Xu, Xiaoqing, Wang, Jiaming, Zhou, Wenkai, Wang, Xin, Wang, Bingjing, Song, Jiaying, Quan, Yuan, Chai, Yangyang, Xu, Henan, Cao, Xuetao

2024

Overview

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.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: Animals / Antigen presentation / Antigen Presentation - immunology / Antigens / Biosynthesis / Cancer / Cancer immunotherapy / Cancer Research / Care and treatment / CD8 antigen / Cell activation / Cell Line, Tumor / Cells / CIITA protein / Cytotoxicity / Development and progression / Disease Progression / Flow cytometry / Genetic engineering / Hematology / Humans / Immune evasion / Immune response / Immunogenicity / Immunohistochemistry / Immunosuppression / Immunotherapy / Inoculation / Interferon regulatory factor 1 / IRF1 / Lymphocytes / Lymphocytes T / Major histocompatibility complex / Medicine / Medicine & Public Health / Metastases / MHC / Mice / Mice, Inbred C57BL / Mutation / Neoplasms - immunology / Neoplasms - pathology / Nuclear Proteins - genetics / Nuclear Proteins - immunology / Nucleoli / Nucleophosmin / Oncology / Oncology, Experimental / Proteins / Ribonucleic acid / RNA / Survival analysis / T cells / Tumor cells / Tumor Escape - immunology / Tumor microenvironment / Tumor Microenvironment - immunology / Tumors