Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells.
Hypoxia Supports Differentiation of Terminally Exhausted CD8 T Cells.
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缺氧支持最终耗尽的 CD8 T 细胞的分化。
DOI：
10.3389/fimmu.2021.660944
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发表时间：
2021
影响因子：
7.3
通讯作者：
Croci DO
中科院分区：
文献类型：
--
作者：
Bannoud N;Dalotto-Moreno T;Kindgard L;García PA;Blidner AG;Mariño KV;Rabinovich GA;Croci DO
缺氧、血管生成和免疫抑制被认为是相互关联的事件，它们促进肿瘤进展并损害抗肿瘤治疗的临床有效性。在这里，我们提出了新的机制数据，强调缺氧在微调CD 8 T细胞体外耗竭的作用，试图调和似乎相反的证据缺氧对耗尽的CD 8 T细胞的功能特征的影响。关注最近表征的终末分化和祖细胞耗尽的CD 8 T细胞，我们发现缺氧及其调节介质血管内皮生长因子（VEGF）-A，以PD-1 + TIM-3-祖细胞样亚群为代价促进PD-1 + TIM-3+ CXCR 5+终末耗竭样CD 8 T细胞的分化，而不影响肿瘤坏死因子（TNF）-α和干扰素（IFN）-γ产生或颗粒酶B（GZMB）表达。有趣的是，缺氧加重了耗尽的CD 8 T细胞中的促血管生成分泌特征。VEGF-A是缺氧条件下耗竭的CD 8 T细胞差异分泌的主要因子。在这个意义上，我们发现VEGF-A有助于在体外分化过程中产生终末耗竭的CD 8 T细胞。总之，我们的研究结果突出了缺氧，血管生成和免疫抑制之间的相互调节，提供了一个合理的基础，以优化抗血管生成和免疫抑制策略的协同组合，提高这些治疗的疗效的总体目标。
Hypoxia, angiogenesis, and immunosuppression have been proposed to be interrelated events that fuel tumor progression and impair the clinical effectiveness of anti-tumor therapies. Here we present new mechanistic data highlighting the role of hypoxia in fine-tuning CD8 T cell exhaustion in vitro, in an attempt to reconcile seemingly opposite evidence regarding the impact of hypoxia on functional features of exhausted CD8 T cells. Focusing on the recently characterized terminally-differentiated and progenitor exhausted CD8 T cells, we found that both hypoxia and its regulated mediator, vascular endothelial growth factor (VEGF)-A, promote the differentiation of PD-1+ TIM-3+ CXCR5+ terminally exhausted-like CD8 T cells at the expense of PD-1+ TIM-3- progenitor-like subsets without affecting tumor necrosis factor (TNF)-α and interferon (IFN)-γ production or granzyme B (GZMB) expression by these subpopulations. Interestingly, hypoxia accentuated the proangiogenic secretory profile in exhausted CD8 T cells. VEGF-A was the main factor differentially secreted by exhausted CD8 T cells under hypoxic conditions. In this sense, we found that VEGF-A contributes to generation of terminally exhausted CD8 T cells during in vitro differentiation. Altogether, our findings highlight the reciprocal regulation between hypoxia, angiogenesis, and immunosuppression, providing a rational basis to optimize synergistic combinations of antiangiogenic and immunotherapeutic strategies, with the overarching goal of improving the efficacy of these treatments.
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影响因子：
50.3
作者：
Hanahan, Douglas;Coussens, Lisa M.
通讯作者：
Coussens, Lisa M.
影响因子：
15.9
作者：
Baitsch, Lukas;Baumgaertner, Petra;Speiser, Daniel E.
通讯作者：
Speiser, Daniel E.
影响因子：
64.5
作者：
Dang EV;Barbi J;Yang HY;Jinasena D;Yu H;Zheng Y;Bordman Z;Fu J;Kim Y;Yen HR;Luo W;Zeller K;Shimoda L;Topalian SL;Semenza GL;Dang CV;Pardoll DM;Pan F
通讯作者：
Pan F
肿瘤内缺氧通过通过TGF-β1在胃癌中诱导调节性T细胞来促进免疫耐受性。
影响因子：
3.7
作者：
Deng B;Zhu JM;Wang Y;Liu TT;Ding YB;Xiao WM;Lu GT;Bo P;Shen XZ
通讯作者：
Shen XZ
DOI：
10.1007/164_2017_29
发表时间：
2018-01-01
期刊：
MECHANISMS OF DRUG RESISTANCE IN CANCER THERAPY
影响因子：
--
作者：
Croci, Diego O.;Mendez-Huergo, Santiago P.;Rabinovich, Gabriel A.
通讯作者：
Rabinovich, Gabriel A.