Rescuing lymphocytes from HLA-G immunosuppressive effects mediated by the tumor microenvironment
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Danli Wu1, Isere Kuiaste2, Philippe Moreau3,4, Edgardo Carosella3,4 and Patricia Yotnda1
1 Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children Hospital, Houston, TX, USA
2 Breast Cancer Center, Baylor College of Medicine, Houston, TX, USA
3 CEA, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Service de Recherches en Hémato-Immunologie (SRHI), Hôpital Saint-Louis, Paris, France
4 Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d’Hématologie, Hôpital Saint-Louis, Paris, France
Patricia Yotnda, email:
Keywords: cancers, immunosuppression, HLA-G, ILT2, lymphocytes
Received: June 13, 2015 Accepted: September 17, 2015 Published: October 09, 2015
Several studies have demonstrated that the antitumor activities of both T and natural killer (NK) effector populations are limited by the immunosuppressive strategies of tumors. In several malignant transformations, the expression of HLA-G by tumor cells rises dramatically, rendering them strongly immunosuppressive. In this study, we postulated that the absence of HLA-G receptors would prevent the immunosuppressive effects of both soluble and membrane-bound HLA-G. Thus, we investigated the therapeutic potential of effector NK cells genetically modified to downregulate the expression of ILT2 (HLA-G receptor) on their cell surfaces. We have shown that the proliferation of modified NK is still dependent on stimulation signals (no malignant transformation). ILT2- NK cells proliferate, migrate, and eliminate HLA-G negative targets cells to the same extent parental NK cells do. However, in the presence of HLA-G positive tumors, ILT2- NK cells exhibit superior proliferation, conjugate formation, degranulation, and killing activities compared to parent NK cells. We tested the effectiveness of ILT2- NK cells in vivo using a xenograft cancer model and found that silencing ILT2 rescued their anti-tumor activity.
We believe that combining ILT2- NK cells with existing therapeutic strategies will strengthen the antitumor response in cancer patients.
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