title: Rescuing lymphocytes from HLA-G immunosuppressive effects mediated by the tumor microenvironment.
abstract: 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.
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children Hospital, Houston, TX, USA.
authors.forename: Danli
authors.initials: D
authors.lastname: Wu
authors.affiliation: Breast Cancer Center, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Isere
authors.initials: I
authors.lastname: Kuiaste
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Service de Recherches en Hémato-Immunologie (SRHI), Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Moreau
authors.affiliation: CEA, Institut des Maladies Emergentes et des Thérapies Innovantes (IMETI), Service de Recherches en Hémato-Immunologie (SRHI), Hôpital Saint-Louis, Paris, France.|Université Paris-Diderot, Sorbonne Paris-Cité, UMR E5, Institut Universitaire d'Hématologie, Hôpital Saint-Louis, Paris, France.
authors.forename: Edgardo
authors.initials: E
authors.lastname: Carosella
authors.affiliation: Center for Cell and Gene Therapy, Baylor College of Medicine, Houston Methodist Hospital, Texas Children Hospital, Houston, TX, USA.
authors.forename: Patricia
authors.initials: P
authors.lastname: Yotnda
mesh_terms: D000818:Animals; D015703:Antigens, CD / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015550:Cell Degranulation; D049109:Cell Proliferation; D002633:Chemotaxis; D018920:Coculture Techniques; D003602:Cytotoxicity, Immunologic; D057809:HEK293 Cells; D059951:HLA-G Antigens / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D006801:Humans; D016219:Immunotherapy, Adoptive / Q000379:methods*; D020014:K562 Cells; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000637:transplantation*; D007938:Leukemia / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology / Q000628:therapy*; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D008213:Lymphocyte Activation; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D010641:Phenotype; D034622:RNA Interference; D011971:Receptors, Immunologic / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D023041:Xenograft Model Antitumor Assays
chemical_list: D015703:Antigens, CD; D059951:HLA-G Antigens; C105299:LILRB1 protein, human; D000075362:Leukocyte Immunoglobulin-like Receptor B1; D011971:Receptors, Immunologic
keywords: HLA-G; ILT2; cancers; immunosuppression; lymphocytes