Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer
Boucher, Y.; Posada, J. M.; Subudhi, S.; Rosario, S. R.; Gu, L.; Kumar, A. S.; Kumra, H.; Mino-Kenudson, M.; Talele, N. P.; Duda, D. G.; Fukumura, D.; Wo, J. Y.; Clark, J. W.; Ryan, D. P.; Fernandez-Del Castillo, C.; Hong, T. S.; Pittet, M. J.; Jain, R. K.
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PurposeAdding 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 (LAPC). 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 DesignWe 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 (OS) of patients. ResultsNeoadjuvant 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 (DC) 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 PDAC lesions with a complete/near complete response. OS was associated with DC and antigen presentation genes for patients treated with FFX+CRT, and with immunosuppression and invasion genes or DC- and blood vessel-related genes for those treated with losartan+FFX+CRT. ConclusionsAdding losartan to FFX+CRT reduced pro-invasion and immunosuppression related genes, which were associated with improved treatment outcomes in patients with LAPC.
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