肿瘤细胞治疗研究
英文原题：Immunogenetic Metabolomics Reveals Key Enzymes That Modulate CAR T-cell Metabolism and Function.
这些数据共同揭示了对 CAR T 细胞代谢重编程的系统性认识，并揭示了改进 CAR T 细胞疗法的潜在靶点。
免疫逃逸是癌症进展的关键步骤，也是当前 T 细胞免疫疗法面临的主要障碍。因此，我们研究能否对 T 细胞进行基因重编程，以利用一种常见的肿瘤内在逃逸机制：癌细胞通过形成代谢条件不利的肿瘤微环境（TME）抑制 T 细胞功能。通过计算机筛选，我们鉴定出 ADA 和 PDK1 这两种代谢调节因子。随后发现，过表达这些基因可增强 CD19 特异性嵌合抗原受体（CAR）T 细胞对相应白血病细胞的细胞溶解作用；反之，ADA 或 PDK1 缺失则削弱这一效应。在 CAR T 细胞中过表达 ADA，可在高浓度腺苷（ADA 底物及 TME 中的免疫抑制代谢物）条件下增强癌细胞杀伤。对这两种工程化 CAR T 细胞进行高通量转录组和代谢组分析，发现其整体基因表达和代谢特征均发生改变。功能和免疫学分析显示，在 CD19 和 HER2 特异性 CAR T 细胞中过表达 ADA 可增强增殖并降低耗竭。在体内结直肠癌模型中，ADA 过表达还提高了 HER2 特异性 CAR T 细胞肿瘤浸润和肿瘤清除能力。综上，这些数据系统揭示了 CAR T 细胞代谢重编程的知识，并提供了改善 CAR T 疗法的潜在靶点。
Immune evasion is a critical step of cancer progression that remains a major obstacle for current T cell-based immunotherapies. Hence, we investigated whether it is possible to genetically reprogram T cells to exploit a common tumor-intrinsic evasion mechanism whereby cancer cells suppress T-cell function by generating a metabolically unfavorable tumor microenvironment (TME). In an in silico screen, we identified ADA and PDK1 as metabolic regulators. We then showed that overexpression (OE) of these genes enhanced the cytolysis of CD19-specific chimeric antigen receptor (CAR) T cells against cognate leukemia cells, and conversely, ADA or PDK1 deficiency dampened this effect. ADA-OE in CAR T cells improved cancer cytolysis under high concentrations of adenosine, the ADA substrate, and an immunosuppressive metabolite in the TME. High-throughput transcriptomics and metabolomics analysis of these CAR T cells revealed alterations of global gene expression and metabolic signatures in both ADA- and PDK1-engineered CAR T cells. Functional and immunologic analyses demonstrated that ADA-OE increased proliferation and decreased exhaustion in CD19-specific and HER2-specific CAR T cells. ADA-OE improved tumor infiltration and clearance by HER2-specific CAR T cells in an in vivo colorectal cancer model. Collectively, these data unveil systematic knowledge of metabolic reprogramming directly in CAR T cells and reveal potential targets for improving CAR T-cell therapy.
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