Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17
Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17
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DOI：
10.1182/blood-2010-07-294389
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发表时间：
2011-06-30
期刊：
影响因子：
20.3
通讯作者：
Rouas-Freiss, Nathalie
中科院分区：
文献类型：
--
作者：
Agaugue, Sophie;Carosella, Edgardo D.;Rouas-Freiss, Nathalie
肿瘤细胞表达HLA-G被认为是肿瘤逃避免疫监视的一种机制。然而，虽然在体外已经证实了人类白细胞抗原-G对抗肿瘤免疫效应的抑制作用，但在体内这一问题仍有待解决。在此背景下，动物模型的发展现在是优先建立的概念的证据，即人类白细胞抗原-G(+)肿瘤细胞发展和耐受宿主体内的抗肿瘤免疫反应。在本研究中，我们首次通过小鼠异种肿瘤模型提供了这种作用的体内证据，该模型基于人的HLA-G和小鼠成对的免疫球蛋白样受体-B(PIR-B)之间的相互作用。我们证明，表达人类白细胞抗原-G的肿瘤细胞通过影响先天免疫和获得性免疫在免疫活性宿主中生长。外周血中CD11b(+)、Gr1(+)、PIR-B+抑制细胞的增多、外周T细胞的丧失以及细胞因子平衡有利于Th2/Th1/Th17是其促进肿瘤生长的主要机制。这些数据首次证明了人类白细胞抗原-G在体内肿瘤逃逸中起着至关重要的作用。最后，用特定的抗体阻断人类白细胞抗原-G的功能，可以抑制肿瘤的体内发展，为肿瘤的治疗提供了一种新的创新策略。(血。2011；117(26)：7021-7031)
The expression of HLA-G by malignant cells has been proposed as a tumor escape mechanism from immunosurveillance. However, although the inhibitory effect of HLA-G on antitumoral immune effectors has been documented in vitro, it remains to be resolved in vivo. In this context, the development of an animal model is now a priority to establish the proof of concept that an HLA-G(+) tumor cell develops and tolerizes the host antitumor immune response in vivo. In the present study, we provide the first in vivo evidence of such a role by a xenotumor model in mice based on the interactions between human HLA-G and the murine paired immunoglobulin-like receptor-B (PIR-B). We demonstrate that human tumor cells expressing HLA-G grow in an immunocompetent host by affecting both innate and adaptive immunity. Expansion of blood myeloid-derived CD11b(+)Gr1(+) PIR-B+ suppressor cells, loss of peripheral T cells, and cytokinic balance in favor of Th2 versus Th1/Th17 constitute the main mechanisms by which HLA-G promotes tumor expansion. These data demonstrate for the first time that HLA-G plays a crucial role in in vivo tumor evasion. Finally, blocking HLA-G function by a specific Ab inhibits the in vivo development of the tumor, offering a new innovative therapeutic strategy in cancer. (Blood. 2011;117(26):7021-7031)