Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.
Blockade of surface-bound TGF-β on regulatory T cells abrogates suppression of effector T cell function in the tumor microenvironment.
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DOI：
10.1126/scisignal.aak9702
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发表时间：
2017-08-29
影响因子：
7.3
通讯作者：
Wolchok JD
中科院分区：
文献类型：
--
作者：
Budhu S;Schaer DA;Li Y;Toledo-Crow R;Panageas K;Yang X;Zhong H;Houghton AN;Silverstein SC;Merghoub T;Wolchok JD
调节性T细胞（Regulatory T cells，Tcells）通过抑制抗原特异性CD 8 + T细胞对肿瘤细胞的杀伤来抑制抗肿瘤免疫。为了更好地理解所涉及的机制，我们使用了分离的B16黑色素瘤肿瘤的体外三维（3D）胶原蛋白-纤维蛋白凝胶培养物。该系统概括了抗黑色素瘤免疫的体内抑制，使得解离的肿瘤细胞抵抗共培养的活化的抗原特异性T细胞的杀伤。当在该系统中培养从Treg耗尽的小鼠切除的肿瘤时，未观察到免疫抑制。中和抗体实验表明，阻断转化生长因子-β（TGF-β）也可防止免疫抑制。免疫抑制依赖于细胞-细胞接触或细胞接近，因为来自胶原蛋白-纤维蛋白凝胶培养物的可溶性因子不抑制T细胞对肿瘤细胞的杀伤。此外，活体双光子显微镜显示，肿瘤特异性Pmel-1效应T细胞与小鼠中的肿瘤驻留TcB发生物理相互作用。单独从B16肿瘤中分离的TGF-β足以抑制CD 8 + T细胞介导的杀伤，这依赖于TGF-β表面结合的TGF-β。CD 8 + T细胞的免疫抑制与溶细胞蛋白颗粒酶B丰度的降低和免疫检查点受体PD-1的细胞表面量的增加相关。这些发现表明，肿瘤微环境中Treg与抗肿瘤T细胞之间的接触以TGF-β依赖性方式抑制抗黑色素瘤免疫，并强调了治疗上抑制瘤内Treg的潜在方法。
Regulatory T cells (Tregs) suppress antitumor immunity by inhibiting the killing of tumor cells by antigen-specific CD8+ T cells. To better understand the mechanisms involved, we used ex vivo three-dimensional (3D) collagen-fibrin gel cultures of dissociated B16 melanoma tumors. This system recapitulated the in vivo suppression of antimelanoma immunity, rendering the dissociated tumor cells resistant to killing by cocultured activated, antigen-specific T cells. Immunosuppression was not observed when tumors excised from Treg-depleted mice were cultured in this system. Experiments with neutralizing antibodies showed that blocking transforming growth factor–β (TGF-β) also prevented immunosuppression. Immunosuppression depended on cell-cell contact or cellular proximity because soluble factors from the collagen-fibrin gel cultures did not inhibit tumor cell killing by T cells. Moreover, intravital, two-photon microscopy showed that tumor-specific Pmel-1 effector T cells physically interacted with tumor-resident Tregs in mice. Tregs isolated from B16 tumors alone were sufficient to suppress CD8+ T cell–mediated killing, which depended on surface-bound TGF-β on the Tregs. Immunosuppression of CD8+ T cells correlated with a decrease in the abundance of the cytolytic protein granzyme B and an increase in the cell surface amount of the immune checkpoint receptor PD-1. These findings suggest that contact between Tregs and antitumor T cells in the tumor microenvironment inhibits antimelanoma immunity in a TGF-β–dependent manner and highlight potential ways to inhibit intratumoral Tregs therapeutically.
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影响因子：
3.7
作者：
Schaer, David A.;Li, Yongbiao;Wolchok, Jedd D.
通讯作者：
Wolchok, Jedd D.
单核细胞CCR2（+）髓样衍生的抑制细胞通过将活化的CD8 T细胞浸润限制在肿瘤微环境中，从而促进免疫逃逸。
影响因子：
11.2
作者：
Lesokhin AM;Hohl TM;Kitano S;Cortez C;Hirschhorn-Cymerman D;Avogadri F;Rizzuto GA;Lazarus JJ;Pamer EG;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
10.1
作者：
Schaer DA;Budhu S;Liu C;Bryson C;Malandro N;Cohen A;Zhong H;Yang X;Houghton AN;Merghoub T;Wolchok JD
通讯作者：
Wolchok JD
DOI：
10.1084/jem.20082205
发表时间：
2009-05-11
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hirschhorn-Cymerman D;Rizzuto GA;Merghoub T;Cohen AD;Avogadri F;Lesokhin AM;Weinberg AD;Wolchok JD;Houghton AN
通讯作者：
Houghton AN
影响因子：
32.4
作者：
Mempel, Thorsten R.;Pittet, Mikael J.;von Andrian, Ulrich H.
通讯作者：
von Andrian, Ulrich H.