肿瘤细胞治疗研究
英文原题：Targeting sphingosine 1-phosphate receptor 3 inhibits T-cell exhaustion and regulates recruitment of proinflammatory macrophages to improve antitumor efficacy of CAR-T cells against solid tumor.
该研究证明，靶向 S1PR3 可增强 CAR-T 细胞疗法的抗肿瘤活性，其机制至少部分是通过抑制 T 细胞耗竭以及通过招募促炎性巨噬细胞重塑 TME 来实现的。
背景：嵌合抗原受体修饰 T（CAR-T）细胞受实体瘤恶劣肿瘤微环境（TME）影响，疗效有限。联合治疗可能是克服这一障碍的有效途径。近期研究显示，鞘氨醇-1-磷酸受体 3（S1PR3）在调节免疫环境方面具有巨大潜力，但 S1PR3 在基于 T 细胞的免疫疗法中的功能意义及其分子机制尚未得到充分阐明。方法：本研究考察 EpCAM 特异性 CAR-T 细胞疗法联合药理学阻断 S1PR3 治疗实体瘤的效果，采用 RNA 测序、流式细胞术、ELISA、细胞和分子免疫学技术以及实体瘤小鼠模型。结果：研究发现，S1PR3 高表达与抗程序性死亡蛋白 1（PD-1）免疫疗法耐药和 T 细胞耗竭增加呈正相关。此外，药理学抑制 S1PR3 可提高抗 PD-1 疗法的疗效。随后，我们在具有免疫功能的小鼠乳腺癌和结肠癌模型中，探索 S1PR3 拮抗剂与小鼠 EpCAM 靶向 CAR-T 细胞联合应用的可能性。结果表明，S1PR3 拮抗剂可显著增强小鼠 EpCAM CAR-T 细胞在体外和体内的疗效。机制方面，S1PR3 拮抗剂可增强 CAR-T 细胞活化、调节中央记忆表型，并在体外减少 CAR-T 细胞耗竭。靶向 S1PR3 还可通过促进巨噬细胞活化并使其向促炎表型极化，招募促炎巨噬细胞，从而重塑 TME，增强 CAR-T 细胞浸润并增加 CD8⁺ T 细胞募集。结论：本研究表明，靶向 S1PR3 至少部分通过抑制 T 细胞耗竭及招募促炎巨噬细胞重塑 TME，增强 CAR-T 细胞的抗肿瘤活性。这些发现为联合使用 S1PR3 抑制剂和 CAR-T 细胞治疗实体瘤提供了进一步依据。
BACKGROUNDS: Chimeric antigen receptor (CAR)-modified T cells (CAR-T) are limited in solid tumors due to the hostile tumor microenvironment (TME). Combination therapy could be a promising approach to overcome this obstacle. Recent studies have shown that sphingosine 1-phosphate receptor (S1PR)3 has tremendous potential in regulating the immune environment. However, the functional significance of S1PR3 in T-cell-based immunotherapies and the molecular mechanisms have not been fully understood. METHODS: Here, we studied the combination of EpCAM-specific CAR T-cell therapy with pharmacological blockade of S1PR3 against solid tumor. We have applied RNA sequencing, flow cytometry, ELISA, cellular/molecular immunological technology, and mouse models of solid cancers. RESULTS: Our study provided evidence that S1PR3 high expression is positively associated with resistance to programmed cell death protein-1 (PD-1)-based immunotherapy and increased T-cell exhaustion. In addition, pharmacological inhibition of S1PR3 improves the efficacy of anti-PD-1 therapy. Next, we explored the possible combination of S1PR3 antagonist with murine EpCAM-targeted CAR-T cells in immunocompetent mouse models of breast cancer and colon cancer. The results indicated that the S1PR3 antagonist could significantly enhance the efficacy of murine EpCAM CAR-T cells in vitro and in vivo. Mechanistically, the S1PR3 antagonist improved CAR-T cell activation, regulated the central memory phenotype, and reduced CAR-T cell exhaustion in vitro. Targeting S1PR3 was shown to remodel the TME through the recruitment of proinflammatory macrophages by promoting macrophage activation and proinflammatory phenotype polarization, resulting in improved CAR-T cell infiltration and amplified recruitment of CD8+T cells. CONCLUSIONS: This work demonstrated targeting S1PR3 could increase the antitumor activities of CAR-T cell therapy at least partially by inhibiting T-cell exhaustion and remodeling the TME through the recruitment of proinflammatory macrophages. These findings provided additional rationale for combining S1PR3 inhibitor with CAR-T cells for the treatment of solid tumor.
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