title: Repeated systemic administrations of both aminobisphosphonates and human Vγ9Vδ2 T cells efficiently control tumor development in vivo.
abstract: Peripheral Vγ9Vδ2 T lymphocytes compose a major γδ T cell subset in primates with broad reactivity against tumor cells. Vγ9Vδ2 T cells are specifically activated by phosphorylated isoprenoid pathway metabolites called "phosphoagonists." Accordingly, pharmacologic inhibitors of the mevalonate pathway, such as aminobisphosphonates (NBP) that upregulate the intracellular production of phosphoagonists, increase antitumor Vγ9Vδ2 T cell responses. Immunotherapeutic protocols exploiting GMP-grade agonist molecules targeting human Vγ9Vδ2 T lymphocytes have yielded promising, yet limited, signs of antitumor efficacy and therefore need to be improved for next-generation immunotherapies. In this study, we used a model of s.c. human tumor xenografts in severely immunodeficient mice to assess the antitumor efficacy of systemic NBP treatments when combined with the adoptive transfer of human Vγ9Vδ2 T cells. We show that infusion of Vγ9Vδ2 T cells, 24 h after systemic NBP treatment, efficiently delays tumor growth in mice. Importantly, our results indicate efficient but transient in vivo NBP-induced sensitization of tumor cells to human Vγ9Vδ2-T cell recognition. Accordingly, repeated and combined administrations of both NBP and γδ T cells yielded improved antitumor responses in vivo. Because Vγ9Vδ2 T cells show similar responsiveness toward both autologous and allogeneic tumors and are devoid of alloreactivity, these results provide preclinical proof of concept for optimized antitumor immunotherapies combining NBP treatment and adoptive transfer of allogeneic human γδ T cells.
authors.affiliation: INSERM, Unité Mixte de Recherche 892 Centre de Recherche en Cancérologie Nantes Angers, Nantes, F-44000, France.
authors.forename: Thibault
authors.initials: T
authors.lastname: Santolaria
authors.forename: Myriam
authors.initials: M
authors.lastname: Robard
authors.forename: Alexandra
authors.initials: A
authors.lastname: Léger
authors.forename: Véronique
authors.initials: V
authors.lastname: Catros
authors.forename: Marc
authors.initials: M
authors.lastname: Bonneville
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Scotet
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology / Q000628:therapy*; D000818:Animals; D045744:Cell Line, Tumor / Q000637:transplantation; D004164:Diphosphonates / Q000008:administration & dosage / Q000627:therapeutic use*; D004334:Drug Administration Schedule; D006801:Humans; D007153:Immunologic Deficiency Syndromes / Q000235:genetics / Q000276:immunology; D016219:Immunotherapy, Adoptive; D008213:Lymphocyte Activation; D008297:Male; D008798:Mevalonic Acid / Q000378:metabolism; D051379:Mice; D008817:Mice, Mutant Strains; D016513:Mice, SCID; D000077268:Pamidronate; D011471:Prostatic Neoplasms / Q000473:pathology / Q000628:therapy*; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000032:analysis / Q000276:immunology; D016176:T-Lymphocyte Subsets / Q000737:chemistry / Q000276:immunology / Q000637:transplantation*; D023041:Xenograft Model Antitumor Assays
chemical_list: D004164:Diphosphonates; D016692:Receptors, Antigen, T-Cell, gamma-delta; C521523:T-cell receptor Vdelta2, human; C521522:T-cell receptor Vgamma9, human; D000077268:Pamidronate; D008798:Mevalonic Acid