肿瘤细胞治疗研究
英文原题：Boosting the Activity of Melanoma-Targeting CAR-T Cells in the Presence of Citrate by the Application of Gluconate.
这些数据共同表明，用葡萄糖酸盐拮抗柠檬酸盐介导的肿瘤生长增强，可能提高 CAR-T 细胞对黑色素瘤的细胞毒性活性。
背景：嵌合抗原受体（CAR）T细胞可治愈部分血液系统恶性肿瘤患者，但在实体瘤中会遭遇免疫抑制性肿瘤微环境（TME），严重限制其细胞毒能力。柠檬酸在TME中积聚，是介导免疫抑制的重要代谢物，且癌细胞可利用柠檬酸促进多种肿瘤（包括黑色素瘤）生长；使用葡萄糖酸阻断柠檬酸转运蛋白pmCiC可消除柠檬酸介导的肿瘤生长。 方法：为增强黑色素瘤治疗，我们探索将葡萄糖酸用作CAR-T细胞疗法的辅助药物。 结果：首先，在基于反复使用相应癌细胞刺激抗原的“压力测试”中，葡萄糖酸未损害CAR-T细胞的细胞毒性、细胞因子分泌和持久性。加入葡萄糖酸可拮抗柠檬酸介导的黑色素瘤细胞增殖增强。因此，在葡萄糖酸存在时，CSPG4特异性CAR-T细胞对柠檬酸促进的黑色素瘤细胞的清除能力增强。 结论：总体而言，这些数据提示，使用葡萄糖酸抵消柠檬酸介导的肿瘤生长增强，可能提高CAR-T细胞对黑色素瘤的细胞毒活性。
Background: Chimeric antigen receptor (CAR) T cells achieve cure in the therapy of hematological malignancies. In solid tumors, however, CAR-T cells face an immunosuppressive tumor microenvironment (TME) which crucially impedes their cytotoxic capacities. Citrate accumulating in the TME is a crucial metabolite in mediating immune suppression and is consumed by cancer cells promoting growth of various tumors, including melanoma; blocking the citrate transporter pmCiC with gluconate abrogates citrate-mediated tumor growth. Methods: To bolster treatment of melanoma, we explored gluconate as adjuvant for CAR-T cell therapy. Results: First, gluconate did not impair CAR-T cell functional capacities with regard to cytotoxicity, cytokine secretion, and persistence in a "stress test" based on repetitive antigen stimulation with cognate cancer cells. The addition of gluconate antagonized the citrate-mediated enhanced proliferation of melanoma cells. As a consequence, the elimination of citrate-boosted melanoma cells by CSPG4-specific CAR-T cells was augmented in the presence of gluconate. Conclusions: Taken together, these data suggest that counteracting citrate-mediated enhanced tumor growth with gluconate may improve the cytotoxic activity of CAR-T cells against melanoma.
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