Commissariat à l'Energie Atomique et aux Energies Alternatives, Institut d'Imagerie BioMédicale, Service de Recherches en Hémato-Immunologie, Paris, France.
Blood. 2011 Jun 30;117(26):7021-31. doi: 10.1182/blood-2010-07-294389. Epub 2011 Apr 11.
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.
恶性细胞表达 HLA-G 被认为是肿瘤逃避免疫监视的一种机制。然而，尽管 HLA-G 对肿瘤杀伤效应器的抑制作用在体外已得到证实，但在体内仍有待解决。在这种情况下，开发动物模型是当务之急，以建立 HLA-G(+)肿瘤细胞在体内发展并耐受宿主抗肿瘤免疫反应的概念验证。在本研究中，我们通过基于人 HLA-G 与鼠配对免疫球蛋白样受体-B（PIR-B）相互作用的异种移植肿瘤模型，提供了这种作用的第一个体内证据。我们证明，表达 HLA-G 的人肿瘤细胞通过影响先天和适应性免疫在免疫活性宿主中生长。血液髓样来源的 CD11b(+)Gr1(+)PIR-B(+)抑制性细胞的扩增、外周 T 细胞的丧失以及有利于 Th2 而非 Th1/Th17 的细胞因子平衡是 HLA-G 促进肿瘤扩张的主要机制。这些数据首次证明 HLA-G 在体内肿瘤逃逸中起着至关重要的作用。最后，通过特异性 Ab 阻断 HLA-G 功能可抑制肿瘤在体内的发展，为癌症提供了一种新的创新性治疗策略。
