Tumor-derived erythropoietin acts as an immunosuppressive switch in cancer immunity

IF 44.7 1区综合性期刊 Q1 MULTIDISCIPLINARY SCIENCES

Science Pub Date : 2025-04-25 DOI:10.1126/science.adr3026

David Kung-Chun Chiu, Xiangyue Zhang, Bowie Yik-Ling Cheng, Qiang Liu, Kazukuni Hayashi, Bo Yu, Ryan Lee, Catherine Zhang, Xiuli An, Jayakumar Rajadas, Nathan E. Reticker-Flynn, Erinn B. Rankin, Edgar G. Engleman

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Abstract

Successful cancer immunotherapy requires a patient to mount an effective immune response against tumors; however, many cancers evade the body’s immune system. To investigate the basis for treatment failure, we examined spontaneous mouse models of hepatocellular carcinoma (HCC) with either an inflamed T cell–rich or a noninflamed T cell–deprived tumor microenvironment (TME). Our studies reveal that erythropoietin (EPO) secreted by tumor cells determines tumor immunotype. Tumor-derived EPO autonomously generates a noninflamed TME by interacting with its cognate receptor EPOR on tumor-associated macrophages (TAMs). EPO signaling prompts TAMs to become immunoregulatory through NRF2-mediated heme depletion. Removing either tumor-derived EPO or EPOR on TAMs leads to an inflamed TME and tumor regression independent of genotype, owing to augmented antitumor T cell immunity. Thus, the EPO/EPOR axis functions as an immunosuppressive switch for antitumor immunity.

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肿瘤来源的促红细胞生成素在癌症免疫中起免疫抑制开关的作用

成功的癌症免疫治疗需要患者对肿瘤产生有效的免疫反应；然而，许多癌症逃避了人体的免疫系统。为了研究治疗失败的基础，我们检测了具有炎症T细胞丰富或非炎症T细胞缺失肿瘤微环境（TME）的自发性肝细胞癌（HCC）小鼠模型。我们的研究表明，肿瘤细胞分泌的促红细胞生成素（EPO）决定了肿瘤的免疫类型。肿瘤源性EPO通过与肿瘤相关巨噬细胞（tam）上的同源受体EPOR相互作用，自主产生非炎症性TME。EPO信号通过nrf2介导的血红素耗竭促使tam发挥免疫调节作用。由于增强的抗肿瘤T细胞免疫，去除肿瘤源性EPO或TAMs上的EPOR会导致炎症性TME和肿瘤消退，与基因型无关。因此，EPO/EPOR轴作为抗肿瘤免疫的免疫抑制开关。

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来源期刊

Science 综合性期刊-综合性期刊

CiteScore

61.10

自引率

0.90%

发文量

审稿时长

2.1 months

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