Purpose: Adding losartan to FOLFIRINOX (FFX) chemotherapy followed by chemoradiation (CRT) resulted in 61% R0 surgical resection in our phase II trial in patients with locally advanced pancreatic cancer. Here we identify potential mechanisms of benefit by assessing the effects of neoadjuvant losartan+FFX+CRT versus FFX+CRT on the stromal tumor microenvironment. Experimental Design: We performed a gene expression analysis of RNA extracted from pancreatic cancer tissue sections and immunofluorescence for cancer cells and immune cells using archived surgical samples from patients treated with losartan+FFX+CRT (NCT01591733), FFX+CRT (NCT01591733) or surgery upfront, without any neoadjuvant therapy. We then assessed whether certain gene sets could stratify the overall survival of patients. Results: Neoadjuvant losartan+FFX+CRT and FFX+CRT increased the expression of genes linked to vascular normalization, transendothelial migration of leukocytes, T cell activation and cytolytic activity, and dendritic cell related genes versus no neoadjuvant treatment. In comparison to FFX+CRT, losartan+FFX+CRT downregulated pro-invasion, immunosuppression, and M2 macrophages related genes, and upregulated genes associated with tumor suppression, including the p53 pathway. Furthermore, immunostaining revealed significantly less residual disease in lesions treated with losartan+FFX+CRT versus FFX+CRT. Losartan+FFX+CRT also reduced CD4+FOXP3+ regulatory T cells in pancreatic cancer lesions with a complete/near complete response. Overall survival was associated with dendritic cell and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or dendritic cell- and blood vessel-related genes for those treated with losartan+FFX+CRT. Conclusions: Adding losartan to FFX+CRT reduced pro-invasion and immunosuppression related genes, which were associated with improved treatment outcomes in patients with locally advanced pancreatic cancer.

Citation Format: Yves Boucher, Jessica M. Posada, Sonu Subudhi, Spencer R. Rosario, Liqun Gu, Ashwin S. Kumar, Heena Kumra, Mari Mino-Kenudson, Nilesh P. Talele, Dan G. Duda, Dai Fukumura, Jennifer Y. Wo, Jeffrey W. Clark, David P. Ryan, Carlos Fernandez-Del Castillo, Theodore S. Hong, Mikael J. Pittet, Rakesh K. Jain. Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer; 2022 Sep 13-16; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2022;82(22 Suppl):Abstract nr C043.