Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.
Up-regulation of PD-L1, IDO, and T(regs) in the melanoma tumor microenvironment is driven by CD8(+) T cells.
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黑色素瘤肿瘤微环境中PD-L1，IDO和T（REGS）的上调由CD8（+）T细胞驱动。
DOI：
10.1126/scitranslmed.3006504
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发表时间：
2013-08-28
影响因子：
17.1
通讯作者：
Gajewski TF
中科院分区：
文献类型：
--
作者：
Spranger S;Spaapen RM;Zha Y;Williams J;Meng Y;Ha TT;Gajewski TF
肿瘤逃避免疫介导的破坏与抑制T细胞活化的免疫抑制机制有关。尽管在一部分患者中可以发现主动免疫应答的证据，包括CD 8 + T细胞浸润，但这些肿瘤并没有被免疫排斥。在目前的报告中，我们表明，它是T细胞炎症肿瘤的子集，表现出三种定义的免疫抑制机制的高表达：吲哚胺-2，3-双加氧酶（IDO），PD-L1/B7-H1，和FoxP 3+调节性T细胞（Tcells），这表明这些抑制途径可能作为负反馈机制，之后，而不是之前，CD 8 + T细胞浸润。在小鼠中的机制研究揭示，在肿瘤微环境中IDO和PD-L1的上调表达以及TcB的募集依赖于CD 8 + T细胞的存在。前者由干扰素-γ驱动，后者由CCR 4结合趋化因子沿着诱导增殖成分的产生驱动。我们的研究结果表明，这些主要的免疫抑制途径本质上是由免疫系统驱动的，而不是由癌细胞精心策划的，这意味着针对负调节免疫检查点的癌症免疫治疗方法可能优先有益于预先存在T细胞炎症肿瘤微环境的患者。
Tumor escape from immune-mediated destruction has been associated with immunosuppressive mechanisms that inhibit T cell activation. Although evidence for an active immune response, including infiltration with CD8+ T cells, can be found in a subset of patients, those tumors are nonetheless not immunologically rejected. In the current report, we show that it is the subset of T cell–inflamed tumors that showed high expression of three defined immunosuppressive mechanisms: indoleamine-2,3-dioxygenase (IDO), PD-L1/B7-H1, and FoxP3+ regulatory T cells (Tregs), suggesting that these inhibitory pathways might serve as negative feedback mechanisms that followed, rather than preceded, CD8+ T cell infiltration. Mechanistic studies in mice revealed that up-regulated expression of IDO and PD-L1, as well as recruitment of Tregs, in the tumor microenvironment depended on the presence of CD8+ T cells. The former was driven by interferon-γ and the latter by a production of CCR4-binding chemokines along with a component of induced proliferation. Our results argue that these major immunosuppressive pathways are intrinsically driven by the immune system rather than being orchestrated by cancer cells, and imply that cancer immunotherapy approaches targeting negative regulatory immune checkpoints might be preferentially beneficial for patients with a preexisting T cell–inflamed tumor microenvironment.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1056/nejmoa1003466
发表时间：
2010-08-19
期刊：
The New England journal of medicine
影响因子：
--
作者：
Hodi FS;O'Day SJ;McDermott DF;Weber RW;Sosman JA;Haanen JB;Gonzalez R;Robert C;Schadendorf D;Hassel JC;Akerley W;van den Eertwegh AJ;Lutzky J;Lorigan P;Vaubel JM;Linette GP;Hogg D;Ottensmeier CH;Lebbé C;Peschel C;Quirt I;Clark JI;Wolchok JD;Weber JS;Tian J;Yellin MJ;Nichol GM;Hoos A;Urba WJ
通讯作者：
Urba WJ
影响因子：
11.2
作者：
Harlin H;Meng Y;Peterson AC;Zha Y;Tretiakova M;Slingluff C;McKee M;Gajewski TF
通讯作者：
Gajewski TF
介导同种异体移植耐受性的FOXP3+ T调节细胞的募集取决于CCR4趋化因子受体。
影响因子：
15.3
作者：
Lee, I;Wang, LQ;Wells, AD;Dorf, ME;Ozkaynak, E;Hancock, WW
通讯作者：
Hancock, WW
DOI：
10.1084/jem.194.6.847
发表时间：
2001-09-17
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Iellem A;Mariani M;Lang R;Recalde H;Panina-Bordignon P;Sinigaglia F;D'Ambrosio D
通讯作者：
D'Ambrosio D