Cancer-associated fibroblast-targeted strategy enhances antitumor immune responses in dendritic cell-based vaccine.
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.
Ohshio Y
，Teramoto K
，Hanaoka J
，Tezuka N
，Itoh Y
，Asai T
，Daigo Y
，Ogasawara K
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Tranilast inhibits the function of cancer-associated fibroblasts responsible for the induction of immune suppressor cell types.
Cancer-associated fibroblasts (CAFs) are the dominant stromal component in the tumour microenvironment (TME), playing critical roles in generation of pro-tumourigenic TME; however, their contribution to suppression of antitumour immune responses has not been fully understood. To elucidate the interaction between CAFs and immune suppressor cells, we examined whether inhibition of CAFs function would impair the induction of immune suppressor cell types in vitro. In this study, we applied an anti-allergic and antifibrotic agent tranilast, which is used clinically, and evaluated a potential of tranilast to serve as a CAFs inhibitor. CAFs that had been isolated from E.G7 or LLC1 tumour-bearing mice were cultured in the presence of tranilast, and thereafter, CAFs functions on the secretion of some soluble factors as well as the induction of immune suppressor cells were evaluated. As a result, tranilast inhibited the proliferation of CAFs and reduced the levels of stromal cell-derived factor-1, prostaglandin E2 and transforming growth factor-β1 from CAFs in a dose-dependent manner. On the other hand, tranilast exerted no inhibitory effects on immune cells at doses under 100 μm. The induction of regulatory T cells and myeloid-derived suppressor cells from their progenitor cells was suppressed in the medium that CAFs had been cultured in the presence of tranilast; however, these findings were not observed when those progenitor cells were cultured in the medium containing tranilast alone. These data demonstrate that tranilast inhibits CAFs function, which is responsible for the induction of immune suppressor cells, and possesses a potential to serve as a specific CAFs inhibitor.
Ohshio Y
，Hanaoka J
，Kontani K
，Teramoto K
... -
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Phenotypic profile of dendritic and T cells in the lymph node of Balb/C mice with breast cancer submitted to dendritic cells immunotherapy.
Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development influenced by various mutations that occur in the tumor cell and by the immune system's status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Strategies using dendritic cells (DCs) or antigen-presenting cells (APCs), therapeutic mode, in cancer have been developed for some time. The proper interaction between DCs and T cells upon antigen presentation is of greatest importance for an antitumor immune response activation. Thus, various receptors on the surface of T cells must be able to recognize ligands that are located on the surface of APCs. However, little is known about the real behavior and interaction forms of CDs and T cells after vaccination. Due to the crucial importance of DCs in an effective anti-tumor immune response activation and the search for compliant results in inducing this response by immunotherapies with DCs, the phenotypic profile of DCs and T cells in lymph nodes obtained from female Balb/C mice with breast cancer induced by 4T1 cells and DCs treated with vaccines was investigated. We evaluated through flow cytometry based on the surface and intracellular molecules marking; as well as the presence of cytokines and chemokines, IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α and TGF-β in the supernatant of the culture of Balb/C lymph nodes by ELISA. The results show that the vaccination with DCs, in the maturation parameters used in this study, was able to stimulate the secretion of cytokines such as IFN-γ and IL-12 and inhibit the secretion of TGF-β and IL-10 in nodal lymph infiltrates, as well as co-stimulatory activating (CD86) and adhesion molecules in DCs and T cells LFA-1/ICAM-1 and inhibit the secretion of CTLA-4 present in lymph nodes. Facts that led to aTh1 profile polarization, immuno competent in relation to breast cancer. We indirectly evaluated the interaction between DCs and T cells dependent on the vaccination with DCs in tumor draining lymph nodes, in breast cancer in Balb/C mice and we believe that, this way, we will be able to achieve a model vaccine protocol in the future, based on the correct interaction between cells that enable the induction of anti-tumor effective response. Breast cancer (BC) is the most common malignant neoplasm and the cause of death by cancer among women worldwide. Its development influenced by various mutations that occur in the tumor cell and by the immune system's status, which has a direct influence on the tumor microenvironment and, consequently, on interactions with non-tumor cells involved in the immunological response. Strategies using dendritic cells (DCs) or antigen-presenting cells (APCs), therapeutic mode, in cancer have been developed for some time. The proper interaction between DCs and T cells upon antigen presentation is of greatest importance for an antitumor immune response activation. Thus, various receptors on the surface of T cells must be able to recognize ligands that are located on the surface of APCs. However, little is known about the real behavior and interaction forms of DCs and T cells after vaccination. Due to the crucial importance of DCs in an effective anti-tumor immune response activation and the search for compliant results in inducing this response by immunotherapies with DCs, the phenotypic profile of DCs and T cells in lymph nodes obtained from female Balb/C mice with breast cancer induced by 4T1 cells and DCs treated with vaccines was investigated. We evaluated through flow cytometry based on the surface and intracellular molecules marking; as well as the presence of cytokines and chemokines, IL-2, IL-4, IL-10, IL-12, IFN-γ, TNF-α and TGF-β in the supernatant of the culture of Balb/C lymph nodes by ELISA. The results show that the vaccination with DCs, in the maturation parameters used in this study, was able to stimulate the secretion of cytokines such as IFN-γ and IL-12 and inhibit the secretion of TGF-β and IL-10 in nodal lymph infiltrates, as well as co-stimulatory activating (CD86) and adhesion molecules in DCs and T cells LFA-1/ICAM-1 and inhibit the secretion of CTLA-4 present in lymph nodes. Facts that led to aTh1 profile polarization, immuno competent in relation to breast cancer. We indirectly evaluated the interaction between DCs and T cells dependent on the vaccination with DCs in tumor draining lymph nodes, in breast cancer in Balb/C mice and we believe that, this way, we will be able to achieve a model vaccine protocol in the future, based on the correct interaction between cells that enable the induction of anti-tumor effective response.
da Cunha A
，Antoniazi Michelin M
，Cândido Murta EF
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