肿瘤细胞治疗研究
英文原题：CAR-T triggers TAM reeducation and adaptive anti-tumor response via TREM2 deficiency or CD40 agonist.
靶向 GPC3 的嵌合抗原受体 (CAR)-T 疗法在肝细胞癌 (HCC) 中临床疗效不佳。
靶向GPC3的嵌合抗原受体（CAR）T细胞治疗肝细胞癌（HCC）的临床疗效不理想。结合临床数据和免疫功能完整的原位HCC模型，我们证明TREM2阳性肿瘤相关巨噬细胞（TAM）是GPC3-CAR-T耐药的关键介质。我们发现，Trem2缺失可与GPC3-CAR-T协同增强肿瘤控制，其机制是扩大内源性肿瘤特异性CD8⁺ T细胞群（而非CAR-T扩增），并通过代谢重编程将TAM重塑为抗肿瘤型CXCL9高表达/SPP1低表达表型。在机制上，该联合策略通过触发JAK-STAT1、激活AMPK和抑制PI3K-AKT-mTOR，增强氧化代谢并抑制糖酵解。关键的是，Trem2缺失会提高CD40表达，使CD40激动剂能够通过激活AMPK和STAT1驱动的CXCL9生成，模拟Trem2缺失的作用。值得注意的是，临床用CD40激动剂sotigalimab同样能在体外增强人CD8⁺ T细胞迁移。我们的研究强调，在GPC3-CAR-T治疗中联合CD40激动剂可能是诱导TAM重塑、增强HCC CAR-T疗效的关键前提。
Chimeric antigen receptor (CAR)-T therapy targeting GPC3 shows unsatisfactory clinical efficacy in hepatocellular carcinoma (HCC). Combining clinical data and the immunocompetent orthotopic HCC model, we demonstrate that TREM2 + tumor-associated macrophages (TAMs) are critical mediators of GPC3-CAR-T resistance. We find that Trem2 deficiency synergizes with GPC3-CAR-T to enhance tumor control by expanding endogenous tumor-specific CD8 + T cells (not CAR-T amplification) and reeducating TAMs to an anti-tumor CXCL9 hi /SPP1 lo phenotype via metabolic reprogramming. Mechanistically, this combination enhances oxidative metabolism while suppressing glycolysis through JAK-STAT1 triggering, AMPK activation, and PI3K-AKT-mTOR inhibition. Crucially, Trem2 deficiency up-regulates CD40 expression, enabling CD40 agonism to phenocopy Trem2-deficiency effects via AMPK activation and STAT1-driven CXCL9 production. Notably, the clinical agonist sotigalimab similarly enhances human CD8 + T cell migration in vitro. Our findings highlight the significance of combining GPC3-CAR-T therapy with CD40 agonist as a critical pre-requisite for eliciting reeducation of TAMs and enhancing the efficacy of CAR-T therapy in HCC.
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