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Abstract C043: Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer

Presented atAACR Special Conference, Pancreatic cancer, Boston, MA, September 13-16, 2022, p. C043
Publication date2022-11-15
Abstract

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.

eng
NoteAbstract publié dans Cancer research, 2022, vol. 82, issue 22, Supplement ; preprint posté sur https://www.medrxiv.org/content/10.1101/2022.06.09.22275912v1
Citation (ISO format)
BOUCHER, Yves et al. Abstract C043: Addition of losartan to FOLFORINOX and chemoradiation downregulates pro-invasion and immunosuppression-associated genes in locally advanced pancreatic cancer. In: AACR Special Conference. Boston, MA. 2022. C043 p. doi: 10.1158/1538-7445.PANCA22-C043
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