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TGF-β inhibition combined with cytotoxic nanomedicine normalizes the tumor microenvironment and improves immune checkpoint inhibition therapy
1 , 1 , 1 , 2 , 3, 4 , 2 , * 1
1  Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, Nicosia, Cyprus
2  Department of Bioengineering, Graduate School of Engineering, The University of Tokyo, Bunkyo, Tokyo, Japan
3  Innovation Center of NanoMedicine, Kawasaki Institute of Industrial Promotion, Kawasaki, Kanagawa, Japan.
4  Policy Alternatives Research Institute, The University of Tokyo, Bunkyo, Tokyo, Japan.


Tumor normalization strategies aim to improve tumor blood vessel functionality (i.e., perfusion) by restoring tumor vessel compression and hyper-permeability. Despite progress in tumor normalization strategies, their combinatorial antitumor effects with nano- immunotherapy remain unexplored. In this presentation, we re-purposed the TGF-β inhibitor tranilast, an approved anti-fibrotic and antihistamine drug, and combined it with Doxil nanomedicine to normalize murine models of triple negative breast cancer, increase perfusion and oxygenation, and enhance delivery and efficacy of Doxil and immune checkpoint blockers (ICBs). Specifically, we employed two triple-negative breast cancer mouse models to primarily evaluate the therapeutic and normalization effects of tranilast combined with Doxil. We demonstrated the optimized normalization effects of tranilast combined with Doxil and extended our analysis to investigate the effect of tumor normalization to the efficacy of ICBs. Combination of tranilast with Doxil caused a pronounced reduction in extracellular matrix components and an increase in the intratumoral vessel diameter and pericytes coverage, indicators of vessel normalization. These modifications resulted in a significant increase in tumor perfusion and oxygenation and enhanced treatment efficacy as indicated by the notable reduction in tumor size. Furthermore, we found that combining tranilast with Doxil nanomedicine, significantly improved infiltration of T cells into the tumor and the immunostimulatory M1 macrophage content and improved the efficacy of the anti-PD-1/anti-CTLA-4 treatment. We condluded that combinatorial treatment of tranilast with Doxil optimizes tumor normalization towards anti-tumor immunity.

Keywords: cancer nanomedicine, nano-immunotherapy, tumor normalization