Reprogramming the immunological microenvironment through radiation and targeting Axl.
Reprogramming the immunological microenvironment through radiation and targeting Axl.
复制标题
通过辐射和靶向AXL重新编程免疫学微环境。
DOI：
10.1038/ncomms13898
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发表时间：
2016-12-23
影响因子：
16.6
通讯作者：
中科院分区：
文献类型：
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作者：
越来越多的证据表明，电离辐射疗法（RT）与检查点免疫疗法相结合，在治疗一部分癌症方面非常有效。为了更好地理解对这种组合的有限反应，我们分析了转基因乳腺癌模型中肿瘤的遗传、微环境和免疫因素。我们确定了两种肿瘤具有相似的生长特征，但不同的RT反应主要是由于抗肿瘤免疫反应。RT和检查点免疫疗法的结合导致了有反应的肿瘤的治愈，而不是无反应的肿瘤。对肿瘤的分析显示，Axl受体酪氨酸激酶在无反应的肿瘤中过表达，Axl敲除导致生长较慢和放射敏感性增加。这些变化与CD 8 + T细胞应答相关，与检查点免疫治疗相结合可以改善这种应答。这些结果表明Axl在通过MHCI抑制抗原呈递和增强细胞因子释放中的新作用，这促进了抑制性骨髓微环境。放射治疗可以增强抗肿瘤免疫反应。在这里，作者表明乳腺癌细胞对辐射的抵抗可能是由于Axl表达通过MHCI抑制抗原呈递，促进NF-κB信号传导，并增强细胞因子释放，促进抑制性骨髓微环境。
Increasing evidence suggests that ionizing radiation therapy (RT) in combination with checkpoint immunotherapy is highly effective in treating a subset of cancers. To better understand the limited responses to this combination we analysed the genetic, microenvironmental, and immune factors in tumours derived from a transgenic breast cancer model. We identified two tumours with similar growth characteristics but different RT responses primarily due to an antitumour immune response. The combination of RT and checkpoint immunotherapy resulted in cures in the responsive but not the unresponsive tumours. Profiling the tumours revealed that the Axl receptor tyrosine kinase is overexpressed in the unresponsive tumours, and Axl knockout resulted in slower growth and increased radiosensitivity. These changes were associated with a CD8+ T-cell response, which was improved in combination with checkpoint immunotherapy. These results suggest a novel role for Axl in suppressing antigen presentation through MHCI, and enhancing cytokine release, which promotes a suppressive myeloid microenvironment. Radiotherapy can enhance the antitumour immune response. Here, the authors show that resistance to radiation in breast cancer cells can be due to Axl expression that suppresses antigen presentation though MHCI, promotes NF-κB signalling, and enhances cytokine release promoting a suppressive myeloid microenvironment.
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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：
64.8
作者：
Finisguerra V;Di Conza G;Di Matteo M;Serneels J;Costa S;Thompson AA;Wauters E;Walmsley S;Prenen H;Granot Z;Casazza A;Mazzone M
通讯作者：
Mazzone M
DOI：
10.1158/1078-0432.ccr-09-0265
发表时间：
2009-09-01
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Dewan MZ;Galloway AE;Kawashima N;Dewyngaert JK;Babb JS;Formenti SC;Demaria S
通讯作者：
Demaria S
影响因子：
8
作者：
通讯作者：
--
影响因子：
7.2
作者：
Grimaldi AM;Simeone E;Giannarelli D;Muto P;Falivene S;Borzillo V;Giugliano FM;Sandomenico F;Petrillo A;Curvietto M;Esposito A;Paone M;Palla M;Palmieri G;Caracò C;Ciliberto G;Mozzillo N;Ascierto PA
通讯作者：
Ascierto PA