(497c) TGF-? Inhibition Combined with Cytotoxic Nanomedicine Normalizes Triple Negative Breast Cancer Microenvironment Towards Anti-Tumor Immunity

Normalizing the tumor microenvironment (TME) consists of restructuring immature and compressed vessels and in the process, improving their functionality. These normalized vessels have increased perfusion and increased drug delivery as well. The techniques have been shown to be successful at TME normalization, and we believe a combination of nanomedicine and immunotherapy treatments would have even stronger results that enhance the efficacy of immunotherapy. So, we chose tranilast, the TGF-β inhibitor, which is an approved antifibrotic and antihistamine drug to combine with Doxil nanomedicine and doxorubicin for two triple-negative breast cancer mouse models. After observing the normalization effects of the combinatorial treatments, we also analyzed the effects on the immune checkpoint inhibitors. The combination treatment of tranilast and Doxil resulted in a decrease of mechanical forces, which we observed by quantifying the area fraction of components of the extracellular matrix. Additionally, we detected an increase in pericyte coverage, blood vessel diameter, and T cell migration from the treatment. These factors indicate TME normalization and resulted in a decrease in tumor growth. Specifically, the T cells migrated far from immunosuppressive CAFs, which caused a greater T cell distribution that can increase the efficacy of immunotherapies. Finally, the combinatorial treatment increased the ratio of anti-tumor M1-like macrophages to immunosuppressive M2-like macrophages. A triple combination of tranilast, Doxil, and a cocktail of immune checkpoint blocking antibodies resulted in the most reduced tumor growth, displaying the positive effects of TME normalization strategies on immunostimulation.