Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy.
Local angiotensin II contributes to tumor resistance to checkpoint immunotherapy.
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局部血管紧张素 II 有助于肿瘤对检查点免疫疗法的抵抗
DOI：
10.1186/s40425-018-0401-3
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发表时间：
2018-09-12
影响因子：
10.9
通讯作者：
Yuan Y
中科院分区：
文献类型：
--
作者：
Xie G;Cheng T;Lin J;Zhang L;Zheng J;Liu Y;Xie G;Wang B;Yuan Y
背景目前的检查点免疫疗法已经显示出通过恢复或激活免疫系统来控制癌症的潜力。然而，多种机制涉及免疫疗法抗性，这限制了检查点抑制剂的临床益处。免疫抑制微环境是介导肿瘤对免疫治疗的原始抗性的重要因素。我们小组先前的报告已经证明，局部血管紧张素II（AngII）主要存在于肿瘤缺氧微环境中，缺氧肿瘤细胞通过缺氧-乳酸-凝乳酶依赖性机制产生AngII。我们发现肿瘤微环境中的局部AngII参与了肿瘤细胞的免疫逃逸，AngII信号传导阻断使肿瘤敏感，检查点免疫疗法此外，AngII信号传导阻断逆转了肿瘤免疫抑制微环境，并且血管紧张素原（AGT，AngII的前体）表达的抑制强烈触发了缺氧小鼠癌细胞中的免疫激活细胞因子谱。更重要的是，AGT沉默结合检查点阻断产生了abscopal效果在耐药tumors.ConclusionOur的研究表明了一个重要的作用，局部血管紧张素II在形成一个肿瘤免疫抑制微环境，其封锁可能会提高肿瘤的敏感性检查点免疫治疗。AngII信号传导阻断剂和免疫检查点阻断剂的组合可能是改善肿瘤对当前检查点免疫疗法的反应的有希望的策略。
BackgroundCurrent checkpoint immunotherapy has shown potential to control cancer by restoring or activating the immune system. Nevertheless, multiple mechanisms are involved in immunotherapy resistance which limits the clinical benefit of checkpoint inhibitors. An immunosuppressive microenvironment is an important factor mediating the original resistance of tumors to immunotherapy. A previous report by our group has demonstrated that local angiotensin II (AngII) predominantly exists in a tumor hypoxic microenvironment where hypoxic tumour cells produced AngII by a hypoxia-lactate-chymase-dependent mechanism.ResultsHere, using 4T1 and CT26 syngeneic mouse tumor models, we found that local AngII in the tumor microenvironment was involved in immune escape of tumour cells and an AngII signaling blockage sensitized tumours to checkpoint immunotherapy. Furthermore, an AngII signaling blockage reversed the tumor immunosuppressive microenvironment, and inhibition of angiotensinogen (AGT, a precursor of AngII) expression strongly triggered an immune-activating cytokine profile in hypoxic mouse cancer cells. More importantly, AGT silencing combined with a checkpoint blockage generated an abscopal effect in resistant tumors.ConclusionOur study demonstrated an important role of local AngII in the formation of a tumor immunosuppressive microenvironment and its blockage may enhance tumor sensitivity to checkpoint immunotherapy. The combination of an AngII signaling blocker and an immune-checkpoint blockage could be a promising strategy to improve tumors responses to current checkpoint immunotherapy.
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影响因子：
64.8
作者：
De Henau O;Rausch M;Winkler D;Campesato LF;Liu C;Cymerman DH;Budhu S;Ghosh A;Pink M;Tchaicha J;Douglas M;Tibbitts T;Sharma S;Proctor J;Kosmider N;White K;Stern H;Soglia J;Adams J;Palombella VJ;McGovern K;Kutok JL;Wolchok JD;Merghoub T
通讯作者：
Merghoub T
DOI：
10.1056/nejmoa1504030
发表时间：
2015-07-02
期刊：
The New England journal of medicine
影响因子：
--
作者：
Larkin J;Chiarion-Sileni V;Gonzalez R;Grob JJ;Cowey CL;Lao CD;Schadendorf D;Dummer R;Smylie M;Rutkowski P;Ferrucci PF;Hill A;Wagstaff J;Carlino MS;Haanen JB;Maio M;Marquez-Rodas I;McArthur GA;Ascierto PA;Long GV;Callahan MK;Postow MA;Grossmann K;Sznol M;Dreno B;Bastholt L;Yang A;Rollin LM;Horak C;Hodi FS;Wolchok JD
通讯作者：
Wolchok JD
影响因子：
5.2
作者：
Campbell DJ
通讯作者：
Campbell DJ
影响因子：
8.8
作者：
Jenkins RW;Barbie DA;Flaherty KT
通讯作者：
Flaherty KT
DOI：
10.1084/jem.187.12.2009
发表时间：
1998-06-15
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Cole KE;Strick CA;Paradis TJ;Ogborne KT;Loetscher M;Gladue RP;Lin W;Boyd JG;Moser B;Wood DE;Sahagan BG;Neote K
通讯作者：
Neote K