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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 ( CAF s) are the dominant stromal component, playing critical roles in generation of the pro‐tumorigenic  TME . We focused on the immunosuppressive trait of  CAF s, and systematically explored the alteration of tumor‐associated immune responses by  CAF ‐targeted therapy. C57 BL /6 mice s.c. bearing syngeneic E.G7 lymphoma,  LLC 1 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 E 2 , 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  CD 8 +  T cells. In addition,  CAF ‐targeted therapy synergistically enhanced multiple types of systemic antitumor immune responses such as the cytotoxic  CD 8 +  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.

Cancer‐associated fibroblast‐targeted strategy enhances antitumor immune responses in dendritic cell‐based vaccine