title: Phosphostim-activated gamma delta T cells kill autologous metastatic renal cell carcinoma.
abstract: Metastatic renal cell carcinoma, inherently resistant to conventional treatments, is considered immunogenic. Indeed, partial responses are obtained after treatment with cytokines such as IL-2 or IFN-alpha, suggesting that the immune system may control the tumor growth. In this study, we have investigated the ability of the main subset of peripheral gammadelta lymphocytes, the Vgamma9Vdelta2-TCR T lymphocytes, to induce an effective cytotoxic response against autologous primary renal cell carcinoma lines. These gammadelta T cells were expanded ex vivo using a Vgamma9Vdelta2 agonist, a synthetic phosphoantigen called Phosphostim. From 11 of 15 patients, the peripheral Vgamma9Vdelta2 T cells were amplified in vitro by stimulating PBMCs with IL-2 and Phosphostim molecule. These expanded Vgamma9Vdelta2 T cells express activation markers and exhibit an effector/memory phenotype. They display a selective lytic potential toward autologous primary renal tumor cells and not against renal NC. The lytic activity involves the perforin-granzyme pathway and is mainly TCR and NKG2D receptor dependent. Furthermore, an increased expression of MHC class I-related molecule A or B proteins, known ligands of NKG2D, are detected on primary renal tumor cells. Interestingly, from 2 of the 11 positive cultures in response to Phosphostim, expanded-Vgamma9Vdelta2 T cells present an expression of killer cell Ig-like receptors, suggesting their prior recruitment in vivo. Unexpectedly, on serial frozen sections from three tumors, we observe a gammadelta lymphocyte infiltrate that was mainly composed of Vgamma9Vdelta2 T cells. These results outline that Vgamma9Vdelta2-TCR effectors may represent a promising approach for the treatment of metastatic renal cell carcinoma.
authors.affiliation: Institut National de la Santé et de la Recherche Médicale Unité 487, Institut Fédératif de Recherche 54, Institut Gustave Roussy, Villejuif, France.
authors.forename: Emilie
authors.initials: E
authors.lastname: Viey
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Fromont
authors.forename: Bernard
authors.initials: B
authors.lastname: Escudier
authors.forename: Yannis
authors.initials: Y
authors.lastname: Morel
authors.forename: Sylvie
authors.initials: S
authors.lastname: Da Rocha
authors.forename: Salem
authors.initials: S
authors.lastname: Chouaib
authors.forename: Anne
authors.initials: A
authors.lastname: Caignard
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000941:Antigens / Q000276:immunology / Q000494:pharmacology; D002292:Carcinoma, Renal Cell / Q000276:immunology* / Q000473:pathology* / Q000556:secondary; D002454:Cell Differentiation / Q000276:immunology; D045744:Cell Line, Tumor; D003602:Cytotoxicity, Immunologic; D011756:Diphosphates / Q000276:immunology* / Q000494:pharmacology; D005260:Female; D006801:Humans; D016130:Immunophenotyping; D007680:Kidney Neoplasms / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D007694:Killer Cells, Natural / Q000276:immunology / Q000378:metabolism; D007963:Leukocytes, Mononuclear / Q000276:immunology / Q000473:pathology; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000276:immunology / Q000473:pathology; D008297:Male; D008875:Middle Aged; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta / Q000819:agonists / Q000096:biosynthesis / Q000502:physiology*; D011971:Receptors, Immunologic / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; D016176:T-Lymphocyte Subsets / Q000276:immunology* / Q000378:metabolism
chemical_list: D000941:Antigens; D011756:Diphosphates; C527085:KLRK1 protein, human; D055655:NK Cell Lectin-Like Receptor Subfamily K; D016692:Receptors, Antigen, T-Cell, gamma-delta; D011971:Receptors, Immunologic; D054340:Receptors, KIR; D055607:Receptors, Natural Killer Cell; C429553:bromohydrin pyrophosphate