title: Adoptive cytotoxic T lymphocyte therapy triggers a counter-regulatory immunosuppressive mechanism via recruitment of myeloid-derived suppressor cells.
abstract: Complex interactions among multiple cell types contribute to the immunosuppressive milieu of the tumor microenvironment. Using a murine model of adoptive T-cell immunotherapy (ACT) for B16 melanoma, we investigated the impact of tumor infiltrating cells on this complex regulatory network in the tumor. Transgenic pmel-1-specific cytotoxic T lymphocytes (CTLs) were injected intravenously into tumor-bearing mice and could be detected in the tumor as early as on day 1, peaking on day 3. They produced IFN-γ, exerted anti-tumor activity and inhibited tumor growth. However, CTL infiltration into the tumor was accompanied by the accumulation of large numbers of cells, the majority of which were CD11b(+) Gr1(+) myeloid-derived suppressor cells (MDSCs). Notably, CD11b(+) Gr1(int) Ly6G(-) Ly6C(+) monocytic MDSCs outnumbered the CTLs by day 5. They produced nitric oxide, arginase I and reactive oxygen species, and inhibited the proliferation of antigen-specific CD8(+) T cells. The anti-tumor activity of the adoptively-transferred CTLs and the accumulation of MDSCs both depended on IFN-γ production on recognition of tumor antigens by the former. In CCR2(-/-) mice, monocytic MDSCs did not accumulate in the tumor, and inhibition of tumor growth by ACT was improved. Thus, ACT triggered counter-regulatory immunosuppressive mechanism via recruitment of MDSCs. Our results suggest that strategies to regulate the treatment-induced recruitment of these MDSCs would improve the efficacy of immunotherapy.
authors.affiliation: Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo, Japan; MEDINET Co., Ltd., Yokohama, Japan.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hosoi
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Matsushita
authors.forename: Kanako
authors.initials: K
authors.lastname: Shimizu
authors.forename: Shin-Ichiro
authors.initials: S
authors.lastname: Fujii
authors.forename: Satoshi
authors.initials: S
authors.lastname: Ueha
authors.forename: Jun
authors.initials: J
authors.lastname: Abe
authors.forename: Makoto
authors.initials: M
authors.lastname: Kurachi
authors.forename: Ryuji
authors.initials: R
authors.lastname: Maekawa
authors.forename: Kouji
authors.initials: K
authors.lastname: Matsushima
authors.forename: Kazuhiro
authors.initials: K
authors.lastname: Kakimi
mesh_terms: D000818:Animals; D001119:Arginase / Q000096:biosynthesis; D039481:CD11b Antigen / Q000378:metabolism; D049109:Cell Proliferation; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology; D007165:Immunosuppression Therapy; D016219:Immunotherapy, Adoptive / Q000379:methods*; D007371:Interferon-gamma / Q000096:biosynthesis / Q000378:metabolism*; D008297:Male; D008546:Melanoma, Experimental / Q000276:immunology* / Q000628:therapy; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D022423:Myeloid Cells / Q000276:immunology / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000276:immunology*; D009569:Nitric Oxide / Q000096:biosynthesis; D017382:Reactive Oxygen Species / Q000378:metabolism; D054390:Receptors, CCR2 / Q000172:deficiency / Q000235:genetics; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology* / Q000378:metabolism; D059016:Tumor Microenvironment
chemical_list: D039481:CD11b Antigen; C515335:Ccr2 protein, mouse; D017382:Reactive Oxygen Species; D054390:Receptors, CCR2; D009569:Nitric Oxide; D007371:Interferon-gamma; C544448:Arg1 protein, mouse; D001119:Arginase
keywords: CTL; MDSC; adoptive transfer; immunotherapy