Erythropoietin induces tumour progression and CD39 expression on immune cells in a preclinical model of triple-negative breast cancer

IF 4.9 3区 医学 Q2 IMMUNOLOGY Immunology Pub Date : 2024-07-02 DOI:10.1111/imm.13832
Stéphanie Bessoles, Andrada Chiron, Guillaume Sarrabayrouse, Pierre De La Grange, Amine M. Abina, Salima Hacein-Bey-Abina
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Abstract

The adverse effects observed in some cancer patients treated with erythropoiesis-stimulating agents such as erythropoietin (EPO) might be due to the latter's well-known immunosuppressive functions. Here, we used a mouse model of syngeneic triple-negative breast cancer to explore EPO's immunomodulatory role in a tumour setting. Our results showed that EPO treatment promotes tumour growth, exacerbates the ‘immune desert’, and results in a ‘cold tumour’. EPO treatment changed the immune cell distribution in peripheral blood, secondary lymphoid organs, and the tumour microenvironment (TME). Our in-depth analysis showed that EPO mainly impacts CD4 T cells by accelerating their activation in the spleen and thus their subsequent exhaustion in the TME. This process is accompanied by a general elevation of CD39 expression by several immune cells (notably CD4 T cells in the tumour and spleen), which promotes an immunosuppressive TME. Lastly, we identified a highly immunosuppressive CD39+ regulatory T cell population (ICOS+, CTLA4+, Ki67+) as a potential biomarker of the risk of EPO-induced tumour progression. EPO displays pleiotropic immunosuppressive functions and enhances mammary tumour progression in mice.

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在三阴性乳腺癌临床前模型中,促红细胞生成素诱导肿瘤进展和免疫细胞上 CD39 的表达。
在使用促红细胞生成素(EPO)等促红细胞生成药物治疗的一些癌症患者身上观察到的不良反应可能是由于后者众所周知的免疫抑制功能。在这里,我们利用小鼠三阴性乳腺癌模型来探讨 EPO 在肿瘤环境中的免疫调节作用。我们的研究结果表明,EPO治疗会促进肿瘤生长,加剧 "免疫荒漠",并导致 "冷肿瘤"。EPO治疗改变了免疫细胞在外周血、次级淋巴器官和肿瘤微环境(TME)中的分布。我们的深入分析显示,EPO 主要通过加速 CD4 T 细胞在脾脏中的活化,进而加速其在肿瘤微环境中的衰竭来影响它们。在这一过程中,一些免疫细胞(尤其是肿瘤和脾脏中的 CD4 T 细胞)的 CD39 表达普遍升高,从而促进了免疫抑制性 TME。最后,我们发现高度免疫抑制的 CD39+ 调节性 T 细胞群(ICOS+、CTLA4+、Ki67+)是 EPO 诱导肿瘤进展风险的潜在生物标志物。EPO具有多向性免疫抑制功能,能促进小鼠乳腺肿瘤的进展。
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来源期刊
Immunology
Immunology 医学-免疫学
CiteScore
11.90
自引率
1.60%
发文量
175
审稿时长
4-8 weeks
期刊介绍: Immunology is one of the longest-established immunology journals and is recognised as one of the leading journals in its field. We have global representation in authors, editors and reviewers. Immunology publishes papers describing original findings in all areas of cellular and molecular immunology. High-quality original articles describing mechanistic insights into fundamental aspects of the immune system are welcome. Topics of interest to the journal include: immune cell development, cancer immunology, systems immunology/omics and informatics, inflammation, immunometabolism, immunology of infection, microbiota and immunity, mucosal immunology, and neuroimmunology. The journal also publishes commissioned review articles on subjects of topical interest to immunologists, and commissions in-depth review series: themed sets of review articles which take a 360° view of select topics at the heart of immunological research.
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