近日，德国科隆大学教授Roland T. Ullrich及其团队揭示了CSF1R+骨髓单核细胞驱动CAR-T细胞抵抗侵袭性B细胞淋巴瘤。相关论文于2025年6月12日发表在《癌细胞》杂志上。

为了阐明与CAR-T治疗耐药相关的因素，该研究组对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，小组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。在自体甲状腺淋巴瘤母瘤模型中，联合抗CD19 CAR-T细胞治疗与CSF1R阻断表现出协同效应并提高了生存率。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。

据了解，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。

附：英文原文

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

Author: David Stahl, Philipp Gdel, Hyatt Balke-Want, Rahil Gholamipoorfard, Paul Segbers, Luis Tetenborg, Mirjam Koker, Janina Drr, Lisa Gregor, Daniel Bachurski, France Rose, Adrian G. Simon, Zinaida Good, Josefine Jakob, Bjrn Hupl, Marieke Nill, Ruth Flümann, Tobias Riet, Dinah Lange, Stuart J. Blakemore, Herrad Baurmann, Conrad-Amadeus Voltin, Nicole Potter, Lilli Schlzer, Max Freihammer, Svenja Wagener-Ryczek, Andra-Iza Iuga, Jan-Michel Heger, Hanna Ludwig, Julia K. Schleifenbaum, Jessica Propp, Paul J. Brckelmann, Ron D. Jachimowicz, Gero Knittel, Sven Borchmann, Sabine Merkelbach-Bruse, Christian Pallasch, Martin Peifer, Jan Rybniker, Alexander Quaas, Mark Nitz, Johannes Brgelmann, Werner Müller, Thorsten Persigehl, Katarzyna Bozek, Sebastian J. Theobald

Issue&Volume: 2025-06-12

Abstract: 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.

DOI: 10.1016/j.ccell.2025.05.013

Source: https://www.cell.com/cancer-cell/abstract/S1535-6108(25)00222-3