CSF1R+骨髓单核细胞驱动CAR-T细胞抵抗侵袭性B细胞淋巴瘤

IF 48.8 1区医学 Q1 CELL BIOLOGY

Cancer Cell Pub Date : 2025-06-12 DOI:10.1016/j.ccell.2025.05.013

David Stahl, Philipp Gödel, Hyatt Balke-Want, Rahil Gholamipoorfard, Paul Segbers, Luis Tetenborg, Mirjam Koker, Janina Dörr, Lisa Gregor, Daniel Bachurski, France Rose, Adrian G. Simon, Zinaida Good, Josefine Jakob, Björn Häupl, Marieke Nill, Ruth Flümann, Tobias Riet, Dinah Lange, Stuart J. Blakemore, Roland T. Ullrich

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引用次数: 0

摘要

尽管有改善，但大约60%的复发或难治性（r/r）侵袭性B细胞淋巴瘤（B- nhl）患者不能从CAR-T细胞治疗中获得持久的益处。为了阐明与CAR-T治疗耐药相关的因素，我们对CAR-T前和CAR-T后细胞标本进行了高维分析。在非持久反应的患者中，我们发现了与预后相关的淋巴瘤相关骨髓单核细胞（LAMM）基因特征。深入分析显示，在人和小鼠B-NHL中，不同的CSF1R+CD14+CD68+ LAMM细胞群抑制CAR-T细胞功能，并与不良预后相关。细胞-细胞推理分析发现，LAMM细胞通过PGE2-EP2/EP4轴直接与LAMM- t细胞相互作用，从而损害CAR-T细胞的功能。在原发性淋巴瘤小鼠模型中，联合抗cd19 CAR-T细胞治疗与CSF1R阻断表现出协同作用并提高生存率。这些发现为联合使用抗cd19 CAR-T细胞和CSF1R抑制剂治疗r/r侵袭性B-NHL患者提供了强有力的理论依据。

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

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

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 PGE₂-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.

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来源期刊

Cancer Cell 医学-肿瘤学

CiteScore

55.20

自引率

1.20%

发文量

179

审稿时长

4-8 weeks

期刊介绍： Cancer Cell is a journal that focuses on promoting major advances in cancer research and oncology. The primary criteria for considering manuscripts are as follows: Major advances: Manuscripts should provide significant advancements in answering important questions related to naturally occurring cancers. Translational research: The journal welcomes translational research, which involves the application of basic scientific findings to human health and clinical practice. Clinical investigations: Cancer Cell is interested in publishing clinical investigations that contribute to establishing new paradigms in the treatment, diagnosis, or prevention of cancers. Insights into cancer biology: The journal values clinical investigations that provide important insights into cancer biology beyond what has been revealed by preclinical studies. Mechanism-based proof-of-principle studies: Cancer Cell encourages the publication of mechanism-based proof-of-principle clinical studies, which demonstrate the feasibility of a specific therapeutic approach or diagnostic test.