title: NK cell adoptive transfer combined with Ontak-mediated regulatory T cell elimination induces effective adaptive antitumor immune responses.
abstract: Previous work from our laboratory showed that hydrocortisone (HC) combined with IL-15 induces expansion of activated human NK cells. We set up an experimental tumor model to evaluate the use of adoptively transferred, HC plus IL-15 (HC/IL-15)-activated and -expanded murine NK cells in the treatment of syngeneic mice carrying established lung metastases of the CT26 transplantable tumor. We also examined the effect of denileukin diftitox (Ontak) on the depletion of regulatory T cells to enhance the in vivo antitumor immunity induced by the adoptively transferred NK cells. Our results clearly demonstrate that murine DX5(+) NK cells are largely expanded in the presence of IL-15 plus HC while retaining intact their functional status. Moreover, when intravenously infused, they mediated significant antitumor responses against CT26 lung tumors in syngeneic BALB/c animals that were further enhanced upon pretreatment of the tumor-bearing animals with Ontak. Total splenocytes and isolated splenic T cells from NK-treated mice responded in vitro against CT26 tumor cells as evidenced by IFN-γ-based ELISPOT, proliferation, and cytotoxicity assays. Importantly, animals treated with Ontak plus adoptive transfer of HC/IL-15-expanded NK cells significantly retarded CT26 tumor growth after a rechallenge with the same tumor s.c. in their flanks. Taken altogether, our data suggest that NK cell adoptive transfer can trigger adaptive antitumor T cell responses, and regulatory T cell depletion by Ontak is mandatory for enabling HC/IL-15-activated NK cells to promote long-lasting adaptive antitumor immunity.
authors.affiliation: Cancer Immunology and Immunotherapy Center, Saint Savas Cancer Hospital, Athens 115 22, Greece.
authors.forename: Maria
authors.initials: M
authors.lastname: Salagianni
authors.forename: Eftychia
authors.initials: E
authors.lastname: Lekka
authors.forename: Ardiana
authors.initials: A
authors.lastname: Moustaki
authors.forename: Eleni G
authors.initials: EG
authors.lastname: Iliopoulou
authors.forename: Constantin N
authors.initials: CN
authors.lastname: Baxevanis
authors.forename: Michael
authors.initials: M
authors.lastname: Papamichail
authors.forename: Sonia A
authors.initials: SA
authors.lastname: Perez
mesh_terms: D056704:Adaptive Immunity; D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D049109:Cell Proliferation / Q000187:drug effects; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000276:immunology / Q000556:secondary; D004167:Diphtheria Toxin / Q000008:administration & dosage / Q000627:therapeutic use*; D006854:Hydrocortisone / Q000008:administration & dosage / Q000627:therapeutic use; D019409:Interleukin-15 / Q000008:administration & dosage; D007376:Interleukin-2 / Q000008:administration & dosage / Q000627:therapeutic use*; D007694:Killer Cells, Natural / Q000166:cytology / Q000276:immunology / Q000637:transplantation*; D008175:Lung Neoplasms / Q000188:drug therapy / Q000276:immunology* / Q000473:pathology; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D051379:Mice; D008807:Mice, Inbred BALB C; D011897:Random Allocation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology* / Q000473:pathology
chemical_list: D000970:Antineoplastic Agents; D004167:Diphtheria Toxin; D019409:Interleukin-15; D007376:Interleukin-2; D011993:Recombinant Fusion Proteins; C078456:denileukin diftitox; D006854:Hydrocortisone