The crosstalk involving immune cells subsets, the components of tumor microenvironment and cancer cells could positively result in the delaying of tumor progression. Then, the use of immunotherapy to generates or stimulates the antitumor immune response and inhibits tumor growth has become an interesting option, especially when is used as adjuvant, for many types of tumors. We have previously demonstrated that the administration of low-dose of cyclophosphamide (Cy), a chemotherapeutic agent able to eliminates the immunosuppression induced by tumors in combination with interleukin 12 based-gene therapy (AdIL-12) has a synergistic antitumoral effect leading to complete regression in 50% of tumors in a murine model of colon adenocarcinoma. The main mechanisms associated with the efficacy of combined therapy were the strongly reduction of CD4+CD25+Foxp3+ T cells and myeloid-derived suppressor cells and the induction of potent specific immune response mediated by cytotoxic interferon gamma (INF-gamma)-producing CD4+ T lymphocytes. Our current aims were to evaluate the effects of 4-methylumbelliferone (4Mu), a selective inhibitor of hyaluronan (HA) synthesis, on tumor microenvironment and to explore how 4Mu affects the therapeutic efficacy of Cy+AdIL-12. The results showed that 4Mu significantly reduced the amount of tumoral HA leading to a significant decrease in tumor interstitial pressure. Importantly, tumor perfusion was improved allowing an increase of adenoviral vector transfection. 4Mu therapy was also able to induce a significantly enhance of trafficking of specific antitumoral lymphocytes. Moreover, the administration of specific cytotoxic lymphocytes in 4Mu treated mice evidenced a potent inhibition on tumor growth. In association with these effects, the combination of 4Mu+Cy+AdIL-12 showed complete regression in more of 70% of tumors and mice treated with the triple combination significantly prolonged their survival. The use of 4Mu+Cy+AdIL-12 also induce a decrease in levels of pro-angiogenic factors such as Vascular Endothelial Growth Factor (VEGF), Hypoxia-inducible Factor 1-alpha (HIF 1-alpha) and interleukin 6 (IL-6), together with an increase of anti-angiogenic molecules (Trombospondin-1 (TSP-1) and Interferon-Inducible protein-10 (IP-10) in tumor milieu. Our results showed that tumor microenvironment remodeling is an interesting strategy to increase the efficacy of anticancer immunotherapies based on gene and/or cell therapy.
Note:This abstract was not presented at the conference.
Citation Format: Mariana Malvicini, Esteban Fiore, Valentina Ghiaccio, Flavia Piccioni, Miguel Rizzo, Mariana Garcia, Marcelo Rodriguez, Juan Bayo, Estanislao Peixoto, Catalina Atorrasagasti, Laura Alaniz, Pablo Matar, Guillermo Mazzolini. 4-methylumbelliferone modulates tumor microenvironment improving the antitumor efficacy of combined gene-based immunotherapy in murine colon adenocarcinoma. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr B178.
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