title: Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine.
abstract: Given the close interaction between tumor cells and stromal cells in the tumor microenvironment (TME), TME-targeted strategies would be promising for developing integrated cancer immunotherapy. Cancer-associated fibroblasts (CAFs) are the dominant stromal component, playing critical roles in generation of the pro-tumorigenic TME. We focused on the immunosuppressive trait of CAFs, and systematically explored the alteration of tumor-associated immune responses by CAF-targeted therapy. C57BL/6 mice s.c. bearing syngeneic E.G7 lymphoma, LLC1 Lewis lung cancer, or B16F1 melanoma were treated with an anti-fibrotic agent, tranilast, to inhibit CAF function. The infiltration of immune suppressor cell types, including regulatory T cells and myeloid-derived suppressor cells, in the TME was effectively decreased through reduction of stromal cell-derived factor-1, prostaglandin E2 , and transforming growth factor-β. In tumor-draining lymph nodes, these immune suppressor cell types were significantly decreased, leading to activation of tumor-associated antigen-specific CD8(+) T cells. In addition, CAF-targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic CD8(+) T cell response, natural killer activity, and antitumor humoral immunity in combination with dendritic cell-based vaccines; however, the suppressive effect on tumor growth was not observed in tumor-bearing SCID mice. These data indicate that systemic antitumor immune responses by various immunologic cell types are required to bring out the efficacy of CAF-targeted therapy, and these effects are enhanced when combined with effector-stimulatory immunotherapy such as dendritic cell-based vaccines. Our mouse model provides a novel rationale with TME-targeted strategy for the development of cell-based cancer immunotherapy.
authors.affiliation: Department of Surgery, Shiga University of Medical Science, Shiga, Japan.
authors.forename: Yasuhiko
authors.initials: Y
authors.lastname: Ohshio
authors.forename: Koji
authors.initials: K
authors.lastname: Teramoto
authors.forename: Jun
authors.initials: J
authors.lastname: Hanaoka
authors.forename: Noriaki
authors.initials: N
authors.lastname: Tezuka
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Itoh
authors.forename: Tohru
authors.initials: T
authors.lastname: Asai
authors.forename: Yataro
authors.initials: Y
authors.lastname: Daigo
authors.forename: Kazumasa
authors.initials: K
authors.lastname: Ogasawara
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000276:immunology*; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects / Q000276:immunology; D019496:Cancer Vaccines / Q000276:immunology*; D045744:Cell Line, Tumor; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000276:immunology*; D007111:Immunity, Cellular / Q000187:drug effects / Q000276:immunology*; D056724:Immunity, Humoral / Q000187:drug effects / Q000276:immunology*; D007167:Immunotherapy / Q000379:methods; D007694:Killer Cells, Natural / Q000187:drug effects / Q000276:immunology; D008198:Lymph Nodes / Q000187:drug effects / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D016513:Mice, SCID; D009369:Neoplasms / Q000188:drug therapy / Q000276:immunology*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D059016:Tumor Microenvironment / Q000187:drug effects / Q000276:immunology; D062367:ortho-Aminobenzoates / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D019496:Cancer Vaccines; D062367:ortho-Aminobenzoates; C012293:tranilast
keywords: Cancer-associated fibroblasts; dendritic cell-based vaccine immunotherapy; suppressor immune cells; tranilast; tumor microenvironment