title: Adoptive transfer of Tc1 or Tc17 cells elicits antitumor immunity against established melanoma through distinct mechanisms.
abstract: Adoptive cell transfer (ACT) of ex vivo-activated autologous tumor-reactive T cells is currently one of the most promising approaches for cancer immunotherapy. Recent studies provided some evidence that IL-17-producing CD8(+) (Tc17) cells may exhibit potent antitumor activity, but the specific mechanisms have not been completely defined. In this study, we used a murine melanoma lung-metastasis model and tested the therapeutic effects of gp100-specific polarized type I CD8(+) cytotoxic T (Tc1) or Tc17 cells combined with autologous bone marrow transplantation after total body irradiation. Bone marrow transplantation combined with ACT of antitumor (gp100-specific) Tc17 cells significantly suppressed the growth of established melanoma, whereas Tc1 cells induced long-term tumor regression. After ACT, Tc1 cells maintained their phenotype to produce IFN-γ, but not IL-17. However, although Tc17 cells largely preserved their ability to produce IL-17, a subset secreted IFN-γ or both IFN-γ and IL-17, indicating the plasticity of Tc17 cells in vivo. Furthermore, after ACT, the Tc17 cells had a long-lived effector T cell phenotype (CD127(hi)/KLRG-1(low)) as compared with Tc1 cells. Mechanistically, Tc1 cells mediated antitumor immunity primarily through the direct effect of IFN-γ on tumor cells. In contrast, despite the fact that some Tc17 cells also secreted IFN-γ, Tc17-mediated antitumor immunity was independent of the direct effects of IFN-γ on the tumor. Nevertheless, IFN-γ played a critical role by creating a microenvironment that promoted Tc17-mediated antitumor activity. Taken together, these studies demonstrate that both Tc1 and Tc17 cells can mediate effective antitumor immunity through distinct effector mechanisms, but Tc1 cells are superior to Tc17 cells in mediating tumor regression.
authors: Department of Immunology, H. Lee Moffitt Cancer Center and Research Institute, Tampa, FL 33612, USA.
authors: Yu
authors: Y
authors: Yu
authors: Hyun-Ii
authors: HI
authors: Cho
authors: Dapeng
authors: D
authors: Wang
authors: Kane
authors: K
authors: Kaosaard
authors: Claudio
authors: C
authors: Anasetti
authors: Esteban
authors: E
authors: Celis
authors: Xue-Zhong
authors: XZ
authors: Yu
mesh_terms: D019264:Adoptive Transfer / Q000379:methods*; D000818:Animals; D016026:Bone Marrow Transplantation / Q000276:immunology / Q000379:methods / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000528:radiation effects / Q000637:transplantation*; D003602:Cytotoxicity, Immunologic / Q000528:radiation effects; D020381:Interleukin-17 / Q000096:biosynthesis* / Q000528:radiation effects; D008175:Lung Neoplasms / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D008213:Lymphocyte Activation / Q000276:immunology; D008546:Melanoma, Experimental / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D014916:Whole-Body Irradiation / Q000379:methods; D058951:gp100 Melanoma Antigen / Q000096:biosynthesis / Q000276:immunology
chemical_list: D020381:Interleukin-17; D058951:gp100 Melanoma Antigen