CELL INTELLIGENCE · 肿瘤细胞治疗研究

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CSF1R(+) 髓系-单核细胞驱动侵袭性 B 细胞淋巴瘤中的 CAR-T 细胞耐药

英文原题：CSF1R(+) myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma.

查看英文原题

CSF1R(+) myeloid-monocytic cells drive CAR-T cell resistance in aggressive B cell lymphoma.

PubMed 2025/06/12（内容时间） Cancer Cell Q1 · IF 56.1（JCR 2025）

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靶点：CD19技术：CAR-TB细胞淋巴瘤淋巴瘤地区：欧洲
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中文摘要

尽管有所改善，约 60% 的复发/难治性 (r/r) 侵袭性 B 细胞淋巴瘤 (B-NHL) 患者未能从 CAR-T 细胞治疗中获得持久获益。为阐明与 CAR-T 治疗耐药相关的因素，我们对 CAR-T 细胞治疗前和治疗后的标本进行了高维分析。在未获得持久缓解的患者中，我们鉴定出一种具有预后相关性的淋巴瘤相关髓系-单核细胞 (LAMM) 基因特征。深入分析揭示，在人类和小鼠 B-NHL 中均存在一个独特的 CSF1R+ CD14+ CD68+ LAMM 细胞群，其抑制 CAR-T 细胞功能并与不良结局相关。细胞间推断分析发现，LAMM 细胞通过 PGE2-EP2/EP4 轴介导的直接 LAMM-T 细胞相互作用损害 CAR-T 细胞功能。在自发性淋巴瘤小鼠模型中，抗 CD19 CAR-T 细胞治疗联合 CSF1R 阻断表现出协同效应并改善生存。这些发现为在治疗 r/r 侵袭性 B-NHL 患者中联合抗 CD19 CAR-T 细胞与 CSF1R 抑制剂提供了强有力的依据。

展开英文摘要原文

Despite the improvement, approximately 60% of patients with relapsed or refractory (r/r) aggressive B cell lymphoma (B-NHL) do not achieve durable benefit from CAR-T cell therapy. To elucidate factors associated with CAR-T therapy resistance, we conducted high-dimensional analyses of pre- and post-CAR-T cell specimens. In patients with non-durable response, we identified a prognostically relevant lymphoma-associated myeloid-monocytic (LAMM) gene signature.

In-depth profiling revealed a distinct CSF1R + CD14 + CD68 + LAMM cell population in both human and murine B-NHL that inhibits CAR-T cell function and correlates with poor outcome. Cell-cell inference analysis uncovered that LAMM cells impair CAR-T cell function through a direct LAMM-T cell interaction via the PGE 2 -EP2/EP4 axis. In an autochthonous lymphoma mouse model, combined anti-CD19 CAR-T cell therapy with CSF1R blockade exhibited synergistic effects and improved survival.

These findings provide strong rationale for combining anti-CD19 CAR-T cells with CSF1R inhibitors in treating r/r aggressive B-NHL patients.

论文信息

作者
Stahl D、Gödel P、Balke-Want H、Gholamipoorfard R、Segbers P、Tetenborg L、Koker M、Dörr J
第一作者单位
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; Mildred Scheel School of Oncology Aachen Bonn Cologne Düsseldorf (MSSO ABCD), Faculty of Medicine and University Hospital of Cologne, Cologne, Germany.Germany
通讯作者单位
Department I of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf, University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany; Center for Molecular Medicine Cologne (CMMC), University of Cologne, Cologne, Germany; Cancer Research Center Cologne Essen (CCCE), Faculty of Medicine and University Hospital Cologne, University of Cologne, Cologne, Germany; National Center for Tumor Diseases (NCT), NCT West, Cologne, Germany. Electronic address: roland.ullrich@uk-koeln.de.Germany
期刊
Cancer cell2025 Aug 11
原文标识
PubMed 40513575　·　DOI 10.1016/j.ccell.2025.05.013

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