肿瘤细胞中GPR65失活通过巨噬细胞重塑驱动抗原非依赖性CAR-T细胞抵抗。

IF 33.3 1区医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2025-05-02 DOI:10.1158/2159-8290.CD-24-0841

Jayadev Mavuluri, Yogesh Dhungana, Lindsay L Jones, Sheetal Bhatara, Hao Shi, Xu Yang, Song-Eun Lim, Noemi Reyes, Hongbo Chi, Jiyang Yu, Terrence L Geiger

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引用次数: 0

摘要

嵌合抗原受体(CAR)-T细胞疗法虽然对CD19+血液系统恶性肿瘤有希望，但往往因复发而面临挫折。我们的研究确定GPR65是影响CAR-T细胞治疗效果的肿瘤特异性决定因素。在人类患者和免疫能力强的b细胞急性淋巴细胞白血病（B-ALL）小鼠模型中，低GPR65表达与CD19+ CAR-T治疗的耐药性相关。小鼠GPR65敲除（GPR65 KO）肿瘤同样表现出耐药性。通过单细胞网络分析，我们发现GPR65缺乏通过增加肿瘤VEGFA水平重塑肿瘤与宿主巨噬细胞的相互作用，导致巨噬细胞扩增和M2优先极化。在GPR65 KO肿瘤中消耗宿主巨噬细胞或通过删除VEGFA，可以恢复CAR-T细胞治疗的反应性。此外，抗vegfa治疗联合CAR-T细胞治疗可显著延长GPR65 KO肿瘤小鼠的生存期。这些发现强调了肿瘤基因表达对肿瘤微环境和随后的CAR-T细胞治疗结果的深远影响。

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GPR65 Inactivation in Tumor Cells Drives Antigen-Independent CAR T-cell Resistance via Macrophage Remodeling.

Significance: The study identifies GPR65 as an important determinant of B-cell acute lymphoblastic leukemia response to CAR T-cell therapy. Notably, GPR65 absence signals CAR T resistance. By emphasizing the therapeutic potential of targeting VEGFA or host macrophages, our study identifies routes to optimize CAR T-cell therapy outcomes in hematologic malignancies via tumor microenvironment manipulation.

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.