Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors.
Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors.
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DOI：
10.18632/oncotarget.7818
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发表时间：
2016-04-26
期刊：
影响因子：
--
通讯作者：
Ertl HC
中科院分区：
文献类型：
--
作者：
Zhang Y;Ertl HC
肿瘤基质对于支持恶性细胞的生长和转移至关重要，为癌症的主动免疫治疗提供了靶点。先前的研究表明，耗尽表达成纤维细胞激活蛋白（FAP）的基质细胞可以减缓肿瘤进展，同时增加肿瘤抗原（TA）特异性T细胞反应。然而，潜在的途径仍然不明确。在这里，我们发现来自荷瘤小鼠的免疫抑制细胞 (ISC) 对 CD8+T 细胞施加代谢应激，这与共抑制剂 PD-1 表达的增加有关。在两种小鼠黑色素瘤模型中，在接种腺病毒载体后，从肿瘤微环境 (TME) 中消除 FAP+ 基质细胞会降低 ISC 的频率和功能。这与 TME 中细胞因子/趋化因子环境的变化以及 ISC 内 STAT6 信号传导活性的降低有关。 FAP+基质细胞耗竭后ISC的减少与疫苗诱导的肿瘤浸润CD8+T细胞的代谢应激减少及其向功能衰竭的延迟进展有关，从而延长荷瘤小鼠的存活时间。
The tumor stroma, which is essential to support growth and metastasis of malignant cells, provides targets for active immunotherapy of cancer. Previous studies have shown that depleting fibroblast activation protein (FAP)-expressing stromal cells reduces tumor progression and concomitantly increases tumor antigen (TA)-specific T cell responses. However the underlying pathways remain ill defined. Here we identify that immunosuppressive cells (ISCs) from tumor-bearing mice impose metabolic stress on CD8+T cells, which is associated with increased expression of the co-inhibitor PD-1. In two mouse melanoma models, depleting FAP+ stroma cells from the tumor microenvironment (TME) upon vaccination with an adenoviral-vector reduces frequencies and functions of ISCs. This is associated with changes in the cytokine/chemokine milieu in the TME and decreased activity of STAT6 signaling within ISCs. Decreases in ISCs upon FAP+stromal cell depletion is associated with reduced metabolic stress of vaccine-induced tumor infiltrating CD8+T cells and their delayed progression towards functional exhaustion, resulting in prolonged survival of tumor-bearing mice.
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DOI：
10.1158/1541-7786.mcr-12-0307
发表时间：
2012-11
期刊：
Molecular cancer research : MCR
影响因子：
--
作者：
Karagiannis GS;Poutahidis T;Erdman SE;Kirsch R;Riddell RH;Diamandis EP
通讯作者：
Diamandis EP
影响因子：
64.5
作者：
Chang CH;Curtis JD;Maggi LB Jr;Faubert B;Villarino AV;O'Sullivan D;Huang SC;van der Windt GJ;Blagih J;Qiu J;Weber JD;Pearce EJ;Jones RG;Pearce EL
通讯作者：
Pearce EL
影响因子：
64.5
作者：
Ho PC;Bihuniak JD;Macintyre AN;Staron M;Liu X;Amezquita R;Tsui YC;Cui G;Micevic G;Perales JC;Kleinstein SH;Abel ED;Insogna KL;Feske S;Locasale JW;Bosenberg MW;Rathmell JC;Kaech SM
通讯作者：
Kaech SM
影响因子：
8
作者：
Comito, G.;Giannoni, E.;Chiarugi, P.
通讯作者：
Chiarugi, P.
胰腺癌中骨髓白细胞和可溶性介质的特征：骨髓源性抑制细胞的重要性
影响因子：
7.2
作者：
Karakhanova, Svetlana;Link, Julia;Bazhin, Alexandr V.
通讯作者：
Bazhin, Alexandr V.