Abstract PO-034: Changes in cancer associated fibroblast subsets following angiotensin II type I receptor blocker (ARB) treatment reduces transient hypoxia and radiation resistance

Abstract

Abstract Poorly oxygenated (hypoxic) tumor cells are resistant to radiation and associated with poor patient outcomes. “Chronically” hypoxic cells develop from limited oxygen diffusion through tumor tissue. Changes in blood vessel perfusion cause fluctuations in oxygen delivery resulting in “transiently” hypoxic cells. Transiently hypoxic cells are often near vasculature and more metastatic than chronically hypoxic cells, identifying transient hypoxia as an important therapeutic target. Angiotensin II receptor (AT1R) type 1 blockers (ARBs) are anti-hypertensive agents with potential anti-fibrotic activity. ARB treatment reduces collagen 1 deposition (Col1) which is thought to occur by targeting AT1R-expressing cancer associated fibroblasts (CAFs) in solid tumors. AT1R signaling is activated through its ligand, angiotensin II (Ang II), which ARBs compete with to inhibit AT1R. It is unclear whether systemic sources of Ang II or localized tumor-derived Ang II contributes to CAF AT1R signaling and collagen deposition. Regardless, ARB-mediated inhibition of Col1 deposition was shown to reduced blood vessel compression and improved perfusion. We recently found that treatment with the ARB telmisartan substantially reduced Col1 deposition, stabilized vascular perfusion, and inhibited the development of transient hypoxia in a human tumor xenograft model. However, it only exhibited a modest reduction in CAF activation. Therefore, we hypothesized that only certain subsets of CAFs are responsible for the development of transient hypoxia in solid tumors, and that AT1R signaling between CAFs and cancer cells may be crucial for initiating the Col1 deposition leading to transient hypoxia development. Recent work by Dr. Mechta-Grigoriou’s group reliably identified four functionally distinct CAF subsets in patient breast and ovarian tumor samples using with a multi-color flow cytometry panel of CAF markers. To distinguish CAF subsets in a murine model, we used a similar flow cytometry panel and indeed, found distinguished subsets of CAFs in various human xenograft murine models. Additionally, we show that crosstalk between cancer cells and cancer associated fibroblasts (CAFs) exists in complementary secretion of Ang II and AT1R by cancer cells and cultured fibroblasts, respectively. This indicates that disruption of this localized Ang II may result in changes in CAF secretion and processing of Col1. We predict that this collaboration of CAFs and tumor cells is responsible for collagen deposition, which leads to blood vessel compression, hypoxia, and reduced radiation response. Citation Format: Che-Min Lee, Brennan J. Wadsworth, Kevin L. Bennewith. Changes in cancer associated fibroblast subsets following angiotensin II type I receptor blocker (ARB) treatment reduces transient hypoxia and radiation resistance [abstract]. In: Proceedings of the AACR Virtual Special Conference on Radiation Science and Medicine; 2021 Mar 2-3. Philadelphia (PA): AACR; Clin Cancer Res 2021;27(8_Suppl):Abstract nr PO-034.