Abstract A18: Angiotensin receptor blockers normalize the pancreatic ductal adenocarcinoma stroma by reprogramming carcinoma-associated fibroblasts
Authors: Liu Hao , Ho William W. , Naxerova Kamila , Grahovac Jelena , Nia Hadi , Chen Ivy , Posada Jessica M. , Schanne Daniel H. , Pinter Matthias , Crain Jonathan , Qi Xialong , Clark Jeffrey W. , Hong Theodore S. , Ryan David P. , Huang Peigen , Lillemoe Keith D. , Castillo Carlos Fernández-Del , Ferrone Cristina R , Downes Michael , Evans Ronald M. , Deshpande Vikram , Boucher Yves , Jain Rakesh K. 
Published: March 2020

Abstract
The resistance to therapy in pancreatic ductal adenocarcinoma (PDAC) is due in part to carcinoma-associated fibroblasts (CAFs) that produce a highly desmoplastic and proinflammatory tumor microenvironment (TME). Our laboratory has shown that the angiotensin receptor blocker (ARB) losartan reduces the CAF-density and desmoplasia, and improves vascular perfusion, and the uptake and efficacy of drugs in animal models of PDAC (Diop-Frimpong et al., PNAS 2011; Chauhan et al., Nature Comm 2013). These preclinical findings led to a phase II trial at Massachusetts General Hospital in locally advanced PDAC patients, which showed that losartan combined with neoadjuvant-FOLFIRINOX chemotherapy followed by chemoradiation more than doubled the resection rate (Murphy et al., JAMA Oncology 2019). Moreover, in a retrospective analysis, we found that the chronic use of angiotensin system inhibitors was independently associated with longer overall survival in nonmetastatic PDAC patients (Liu et al., Clin Cancer Res 2017). However, how ARBs affect CAFs and desmoplasia in human PDAC remains unknown. Here we performed immunohistochemistry in formalin-fixed, paraffin-embedded sections to examine the effect of chronic use of ARB on CAF phenotypes and the extracellular matrix (ECM) in resected PDAC samples from untreated patients and patients treated with ARBs to control their hypertension. We found that the chronic use of ARBs did not reduce the density of CAFs expressing the fibroblast activation protein (FAP), α-smooth muscle actin (α-SMA), or platelet-derived growth factor receptor-beta alone. However, ARBs increased the fraction of CAFs expressing both the angiotensin receptor 1 (AT1) and α-SMA and decreased the fraction of CAFs expressing both AT1 and FAP. ARBs also reduced the intratumoral levels of hyaluronan, suggesting that ARBs reduce desmoplasia in human PDAC. To reveal the underlying mechanisms, we performed a transcriptomic analysis of the bulk tumor as well as α-SMA+ cells isolated from mice bearing orthotopic PDAC tumors and treated with losartan. Gene expression profiling revealed that in both the tumor bulk and α-SMA+ cells, losartan “normalized” the ECM/cytoskeleton interaction, glycosaminoglycan metabolism and platelet-derived growth factor gene sets, and significantly reduced gene transcripts ofS100A8 and S100A9 . Gene products of S100A8 and S100A9 are S100 proteins that stimulate the development of myeloid-derived suppressor cells. In α-SMA+ cells—but not in tumor bulk—losartan reduced cell cycle and muscle contraction gene sets. These results suggest that ARBs can reprogram α-SMA+ cells and normalize the TME in PDAC.
Citation Format: Hao Liu, William W. Ho, Kamila Naxerova, Jelena Grahovac, Hadi Nia, Ivy Chen, Jessica M. Posada, Daniel H. Schanne, Matthias Pinter, Jonathan Crain, Xialong Qi, Jeffrey W. Clark, Theodore S. Hong, David P. Ryan, Peigen Huang, Keith D. Lillemoe, Carlos Fernández-Del Castillo, Cristina R Ferrone, Michael Downes, Ronald M. Evans, Vikram Deshpande, Yves Boucher, Rakesh K. Jain. Angiotensin receptor blockers normalize the pancreatic ductal adenocarcinoma stroma by reprogramming carcinoma-associated fibroblasts [abstract]. In: Proceedings of the AACR Special Conference on Pancreatic Cancer: Advances in Science and Clinical Care; 2019 Sept 6-9; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2019;79(24 Suppl):Abstract nr A18.