肿瘤细胞治疗研究
英文原题：Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment.
Targeting Regnase-1 unleashes CAR T cell antitumor activity for osteosarcoma and creates a proinflammatory tumor microenvironment.
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T细胞功能的负调节因子是增强CAR-T 细胞对实体瘤内在抗肿瘤活性的有前景靶点。然而，实体瘤内源性免疫生态常构成免疫抑制性治疗屏障；目前尚不清楚删除CAR-T 细胞中的负调节因子是否会重塑内源免疫景观。为弥补这一知识空白，我们在免疫功能完整的骨肉瘤模型中开发了靶向B7-H3的CAR-T 细胞，并评估删除强效负调节因子Regnase-1（Reg-1）的内在及外在影响。删除Reg-1不仅改善了B7-H3 CAR-T 细胞的效应功能，还赋予其塑造促炎环境的能力，其特征为产生IFN-γ的内源性T细胞和NK细胞浸润增加，以及包括M2巨噬细胞在内的抑制性髓系细胞减少。因此，删除CAR-T 细胞中的负调节因子可通过形成促炎性肿瘤微环境，建立一种非细胞自主的状态。
Negative regulators of T cell function represent promising targets to enhance the intrinsic antitumor activity of CAR T cells against solid tumors.
However, the endogenous immune ecosystem in solid tumors often represents an immunosuppressive therapeutic barrier to CAR T cell therapy, and it is currently unknown whether deletion of negative regulators in CAR T cells reshapes the endogenous immune landscape. To address this knowledge gap, we developed CAR T cells targeting B7-H3 in immune-competent osteosarcoma models and evaluated the intrinsic and extrinsic effects of deleting a potent negative regulator called Regnase-1 (Reg-1).
Deletion of Reg-1 not only improved the effector function of B7-H3-CAR T cells but also endowed them with the ability to create a proinflammatory landscape characterized by an influx of IFN -producing endogenous T cells and NK cells and a reduction of inhibitory myeloid cells, including M2 macrophages.
Thus, deleting negative regulators in CAR T cells enforces a non-cell-autonomous state by creating a proinflammatory tumor microenvironment.
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