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bioRxiv · 10.1101/2020.06.02.129809

Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice

Selvanesan, B. C.·Meena, K.·Beck, A.·Meheus, L.·Lara, O.·Rooman, I.·Gravekamp, C.
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Abstract

Treatments for pancreatic ductal adenocarcinoma (PDAC) are poorly effective, at least partly due to the tumors immune-suppressive stromal compartment. New evidence of positive effects on immune responses in the tumor microenvironment, compelled us to test the combination of gemcitabine (GEM), a standard chemotherapeutic for pancreatic cancer, with nicotinamide (NAM), the amide form of niacin (vitamin B3), in various mouse tumor models of pancreatic cancer, i.e. peritoneal or orthotopic of Panc-02 (KrasG12D) and orthotopic KPC (KrasG12D, p53R172H, Pdx1-Cre) grafts. A significant reduction in tumor weight and number of metastases was found, as well as a significant improved survival of the NAM+GEM group compared to all control groups. Immunohistochemistry and flow cytometry of pancreatic tumors showed a significant decrease in tumor-associated macrophages (TAM) and myeloid-derived suppressor cells (MDSC), an increase in the number of CD4 and CD8 T cells and the production of granzyme B in the NAM+GEM group. Moreover, T cell responses to tumor-associated antigen survivin were observed in spleens of the mice that received NAM+GEM but not in those that received single agents or saline. In addition, remodeling of the tumor stroma was observed with decreased collagen I and expression of hyaluronic acid binding protein, reorganization of the immune cells into lymph node like structures, and CD31 positive vessels. Expression profiling for a panel of immuno-oncology genes revealed significant changes in genes involved in migration and activation of T cells, attraction of dendritic cells, and epitope spreading. This study highlights the potential of NAM+GEM as immunotherapy for advanced pancreatic cancer.

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Selvanesan, B. C., Meena, K., Beck, A., Meheus, L., Lara, O., Rooman, I., Gravekamp, C.. 2020-06-03. Nicotinamide combined with gemcitabine is an immunomodulatory therapy that restrains pancreatic cancer in mice. https://doi.org/10.1101/2020.06.02.129809

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