Earle A. Chiles Research Institute, Providence Cancer Institute, 4805 NE Glisan St, Portland, OR, 97213, USA.
The Oregon Clinic, Colon and Rectal Surgery Division, 4805 NE Glisan St, Suite 6N60, Portland, OR, 97213, USA.
Nat Commun. 2020 Apr 9;11(1):1749. doi: 10.1038/s41467-020-15404-8.
Transforming growth factor beta (TGFβ) is a multipotent immunosuppressive cytokine. TGFβ excludes immune cells from tumors, and TGFβ inhibition improves the efficacy of cytotoxic and immune therapies. Using preclinical colorectal cancer models in cell type-conditional TGFβ receptor I (ALK5) knockout mice, we interrogate this mechanism. Tumor growth delay and radiation response are unchanged in animals with Treg or macrophage-specific ALK5 deletion. However, CD8αCre-ALK5 (ALK5) mice reject tumors in high proportions, dependent on CD8 T cells. ALK5 mice have more tumor-infiltrating effector CD8 T cells, with more cytotoxic capacity. ALK5-deficient CD8 T cells exhibit increased CXCR3 expression and enhanced migration towards CXCL10. TGFβ reduces CXCR3 expression, and increases binding of Smad2 to the CXCR3 promoter. In vivo CXCR3 blockade partially abrogates the survival advantage of an ALK5 host. These data demonstrate a mechanism of TGFβ immunosuppression through inhibition of CXCR3 in CD8 T cells, thereby limiting their trafficking into tumors.
转化生长因子β（TGFβ）是一种多能免疫抑制细胞因子。TGFβ 将免疫细胞排斥出肿瘤，抑制 TGFβ 可提高细胞毒性和免疫疗法的疗效。我们使用细胞类型条件性 TGFβ 受体 I（ALK5）敲除小鼠的临床前结直肠癌模型来探究这一机制。在 Treg 或巨噬细胞特异性 ALK5 缺失的动物中，肿瘤生长延迟和辐射反应没有改变。然而，CD8αCre-ALK5（ALK5）小鼠以依赖 CD8 T 细胞的方式高比例排斥肿瘤。ALK5 小鼠具有更多浸润肿瘤的效应 CD8 T 细胞，具有更强的细胞毒性。ALK5 缺陷型 CD8 T 细胞表现出更高的 CXCR3 表达和对 CXCL10 的增强迁移。TGFβ 降低 CXCR3 表达，并增加 Smad2 与 CXCR3 启动子的结合。体内 CXCR3 阻断部分消除了 ALK5 宿主的生存优势。这些数据表明 TGFβ 通过抑制 CD8 T 细胞中的 CXCR3 来抑制免疫，从而限制其进入肿瘤的迁移。
