Macrophages are activated toward phagocytic lymphoma cell clearance by pentose phosphate pathway inhibition.

IF 11.7 1区医学 Q1 CELL BIOLOGY

Cell Reports Medicine Pub Date : 2024-12-17 Epub Date: 2024-11-26 DOI:10.1016/j.xcrm.2024.101830

Anna C Beielstein, Elena Izquierdo, Stuart Blakemore, Nadine Nickel, Michael Michalik, Samruddhi Chawan, Reinhild Brinker, Hans-Henrik Bartel, Daniela Vorholt, Lukas Albert, Janica L Nolte, Rebecca Linke, Carolina Raíssa Costa Picossi, Jorge Sáiz, Felix Picard, Alexandra Florin, Jörn Meinel, Reinhard Büttner, Paul Diefenhardt, Sebastian Brähler, Alma Villaseñor, Holger Winkels, Michael Hallek, Marcus Krüger, Coral Barbas, Christian P Pallasch

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引用次数: 0

Abstract

Macrophages in the B cell lymphoma microenvironment represent a functional node in progression and therapeutic response. We assessed metabolic regulation of macrophages in the context of therapeutic antibody-mediated phagocytosis. Pentose phosphate pathway (PPP) inhibition induces increased phagocytic lymphoma cell clearance by macrophages in vitro, in primary human chronic lymphocytic leukemia (CLL) patient co-cultures, and in mouse models. Addition of the PPP inhibitor S3 to antibody therapy achieves significantly prolonged overall survival in an aggressive B cell lymphoma mouse model. PPP inhibition induces metabolic activation and pro-inflammatory polarization of macrophages while it decreases macrophages' support for survival of lymphoma cells empowering anti-lymphoma function. As a mechanism of macrophage repolarization, the link between PPP and immune regulation was identified. PPP inhibition causes decreased glycogen level and subsequent modulation of the immune modulatory uridine diphosphate glucose (UDPG)-Stat1-Irg1-itaconate axis. Thus, we hypothesize the PPP as a key regulator and targetable modulator of macrophage activity in lymphoma to improve efficacy of immunotherapies and prolong survival.

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通过抑制磷酸戊糖途径，激活巨噬细胞清除吞噬性淋巴瘤细胞。

B 细胞淋巴瘤微环境中的巨噬细胞是肿瘤进展和治疗反应的一个功能性节点。我们评估了巨噬细胞在治疗性抗体介导的吞噬作用中的代谢调节。在体外、原发性人类慢性淋巴细胞白血病（CLL）患者共培养物和小鼠模型中，磷酸戊糖途径（PPP）抑制可诱导巨噬细胞增加吞噬淋巴瘤细胞的清除率。在一种侵袭性 B 细胞淋巴瘤小鼠模型中，在抗体疗法中加入 PPP 抑制剂 S3 可显著延长总生存期。PPP 抑制可诱导巨噬细胞的代谢活化和促炎极化，同时降低巨噬细胞对淋巴瘤细胞生存的支持，增强抗淋巴瘤功能。作为巨噬细胞再极化的一种机制，PPP 与免疫调节之间的联系被确定下来。抑制 PPP 会导致糖原水平下降，进而调节免疫调节二磷酸尿苷葡萄糖（UDPG）-Stat1-Irg1-itaconate 轴。因此，我们假设 PPP 是淋巴瘤中巨噬细胞活性的关键调节因子和靶向调节因子，可提高免疫疗法的疗效并延长生存期。

本文章由计算机程序翻译，如有差异，请以英文原文为准。

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来源期刊

Cell Reports Medicine Biochemistry, Genetics and Molecular Biology-Biochemistry, Genetics and Molecular Biology (all)

CiteScore

15.00

自引率

1.40%

发文量

231

审稿时长

40 days

期刊介绍： Cell Reports Medicine is an esteemed open-access journal by Cell Press that publishes groundbreaking research in translational and clinical biomedical sciences, influencing human health and medicine. Our journal ensures wide visibility and accessibility, reaching scientists and clinicians across various medical disciplines. We publish original research that spans from intriguing human biology concepts to all aspects of clinical work. We encourage submissions that introduce innovative ideas, forging new paths in clinical research and practice. We also welcome studies that provide vital information, enhancing our understanding of current standards of care in diagnosis, treatment, and prognosis. This encompasses translational studies, clinical trials (including long-term follow-ups), genomics, biomarker discovery, and technological advancements that contribute to diagnostics, treatment, and healthcare. Additionally, studies based on vertebrate model organisms are within the scope of the journal, as long as they directly relate to human health and disease.