Role of HLA-G in tumor escape through expansion of myeloid-derived suppressor cells and cytokinic balance in favor of Th2 versus Th1/Th17

• Published in: Blood Vol. 117; no. 26; pp. 7021 - 7031
• Main Authors: Agaugué, Sophie, Carosella, Edgardo D., Rouas-Freiss, Nathalie
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 30.06.2011
• Subjects: Adaptive Immunity; Animals; Antigens, Neoplasm - chemistry; Antigens, Neoplasm - metabolism; Cell Line, Tumor; Cell Proliferation; Cytokines - metabolism; Female; Histocompatibility Antigens Class I - chemistry; Histocompatibility Antigens Class I - genetics; Histocompatibility Antigens Class I - immunology; Histocompatibility Antigens Class I - metabolism; HLA Antigens - chemistry; HLA Antigens - genetics; HLA Antigens - immunology; HLA Antigens - metabolism; HLA-G Antigens; Humans; Immunity, Innate; Killer Cells, Natural - immunology; Killer Cells, Natural - metabolism; Mice; Mice, Inbred Strains; Monitoring, Immunologic; Myeloid Cells - immunology; Myeloid Cells - metabolism; Neoplasm Transplantation; Neoplasms - immunology; Neoplasms - metabolism; Neoplasms - pathology; Protein Isoforms - antagonists & inhibitors; Protein Isoforms - genetics; Protein Isoforms - metabolism; Receptors, Immunologic - metabolism; Th1-Th2 Balance; Th2 Cells - immunology; Th2 Cells - metabolism; Tumor Escape
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2010-07-294389

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.