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. 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. 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. 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.

中文翻译：

---

NPM1 抑制肿瘤抗原呈递，促进免疫逃逸和肿瘤进展


肿瘤细胞发展出多种机制来促进其免疫逃避。确定支持免疫逃避的肿瘤内因子可能为癌症免疫治疗提供新的策略。我们旨在探讨肿瘤内因子 NPM1（一种多功能核仁磷蛋白）在癌症免疫逃避和进展中的功能和机制。通过将 Npm1 缺陷的肿瘤细胞皮下接种到同基因小鼠中，检测 NPM1 在肿瘤进展和肿瘤微环境 （TME） 重编程中的作用，然后通过 CyTOF、流式细胞术、免疫组化染色和 RNA-seq 进行探索。观察 OT-1 转基因 T 细胞对 OVA 呈递肿瘤细胞的体外 T 细胞杀伤。NPM1 和 IRF1 的相互作用通过 Co-IP 验证。通过双荧光素酶报告基因测定和 ChIP-qPCR 测定 IRF1 DNA 与 Nlrc5、Ciita 启动子结合中 NPM1 的调节作用。高水平的 NPM1 表达预示着各种人类肿瘤的低存活率。NPM1 缺失抑制肿瘤进展并提高荷瘤小鼠的存活率。Npm1 缺陷型肿瘤显示 CD8+ T 细胞浸润和活化增加，同时免疫抑制细胞的存在减少。Npm1 缺陷增加了 MHC-I 和 MHC-II 分子以及特异性 T 细胞杀伤。从机制上讲，NPM1 与转录因子 IRF1 结合，然后隔离 IRF1 与 Nlrc5 和 Ciita 启动子的结合，以抑制 IRF1 介导的肿瘤细胞中 MHC-I 和 MHC-II 分子的表达。肿瘤内在 NPM1 通过抑制 IRF1 介导的抗原呈递来促进肿瘤免疫逃逸，从而损害肿瘤免疫原性并重新编程免疫抑制 TME。我们的研究将 NPM1 确定为改善癌症免疫治疗的潜在靶点。