Nat Commun:CAR-T细胞通过介导免疫抑制性肿瘤相关巨噬细胞的耗竭增强免疫疗法的疗效

2021-02-16 xiaozeng MedSci原创

免疫抑制性肿瘤微环境(TME)是肿瘤特异性T细胞对癌症有效反应的主要障碍。

免疫抑制性肿瘤微环境(TME)是肿瘤特异性T细胞对癌症有效反应的主要障碍。肿瘤相关巨噬细胞(TAM)是TME的主要组成部分,由表型、转录和功能上截然不同的高度异质性和可塑性巨噬细胞群组成,其可以通过多种机制来支持肿瘤的生长,包括分泌生长因子、基质降解酶和促血管生成因子。

然而,由于巨噬细胞是先天免疫系统不可或缺的一部分,因此某些泛巨噬细胞治疗方法可能会引起全身毒性和/或促炎反应。因此,开发更有效的可应用于临床的药物和方案尤为重要。

FRβ在卵巢癌TME的TAMs中表达

目前包括CAR-T(嵌合抗原受体T细胞)在内的新一代治疗策略可对TME进行重新编程。作为直接靶向癌细胞的常规靶向肿瘤的CAR-T疗法的替代方法,靶向TME非肿瘤成分的疗法已成为一种限制肿瘤发生发展的间接治疗方法。FRβ(叶酸受体β)是一种在急性髓样白血病细胞中表达的糖磷脂酰肌醇锚定的受体,目前已被人为CAR-T细胞疗法的肿瘤抗原靶标。

FRβ CAR-T细胞靶向卵巢癌中FRβ高表达的TAMs

在该研究中,研究人员证实表达FRβ的TAM具有免疫抑制性的M2样特征。在同系肿瘤小鼠模型中,选择性消除CAR-T细胞介导的TME中FRβ+TAM会导致促炎性单核细胞的富集、内源性肿瘤特异性CD8+T细胞的大量涌入,最终抑制了肿瘤的发生发展并延长了生存时间。同样的,通过FRβ特异性CAR-T细胞对TME进行预处理也可以提高肿瘤导向性的抗间皮素CAR-T细胞的效果,而同时使用以上两种CAR-T细胞则不能产生相应的效果。


总而言之,该研究结果揭示了FRβ+TAM在TME中的促肿瘤作用以及靶向消除TAM的药物作为直接靶向肿瘤抗原的常规免疫疗法的制备性辅助药物的治疗意义。


原始出处:

Rodriguez-Garcia, A., Lynn, R.C., Poussin, M. et al. CAR-T cell-mediated depletion of immunosuppressive tumor-associated macrophages promotes endogenous antitumor immunity and augments adoptive immunotherapy. Nat Commun 12, 877 (09 February 2021).

 

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    2021-08-28 仁者大医
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    2021-07-12 liuli5079
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    2021-07-21 liye789132251
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    2021-02-16 内科新手

    谢谢梅斯提供这么好的信息,学到很多

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