Abstract PR-001: Angiotensin II receptor blockers modify the solid tumor microenvironment and improve radiation therapy response
Authors: Wadsworth Brennan J. , Lee Che-Min , Urban Ryan , Hamilton Sarah N. , Bennewith Kevin L. 
Published: April 2021

Abstract
Poorly oxygenated (hypoxic) cells are key components of the solid tumor microenvironment and are well-established contributors to poor therapeutic outcome. Patients with tumors that contain hypoxic cells have worse outcome after radiotherapy, chemotherapy, and surgery, underscoring the therapeutic relevance of hypoxia in driving more aggressive tumor phenotypes. Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are widely prescribed anti-hypertensive agents that inhibit the activity of angiotensin II derived from the renin-angiotensin system. ARBs have also been shown to exhibit anti-fibrotic activity by inhibiting AT1R expressed on myofibroblasts. We recently reported that the ARB telmisartan inhibits collagen I (Col1) deposition in solid tumors, increasing net tumor perfusion, stabilizing microregional tumor blood flow, and decreasing tumor hypoxia. Cancer-associated fibroblasts (CAFs) produce Col1, although recent clinical data indicate the presence of multiple, functionally-diverse CAF subsets in tumors from patients with breast or ovarian cancer. To further explore how ARBs and CAFs affect the solid tumor microenvironment, we were interested in whether murine CAF subsets are present in human tumor xenografts and, if so, whether telmisartan preferentially influences collagen-producing CAF subsets in solid tumors. We were also interested in whether telmisartan affects collagen deposition, hypoxia, and radiation response in head & neck and cervix tumors that are commonly treated with ionizing radiation therapy. We then asked whether head & neck cancer patients taking ARBs as anti-hypertensive medications have quantifiably different tumor microenvironments and improved therapeutic outcome. Using a panel of six human head & neck and cervix tumor xenografts, we identified four unique subsets (S1-S4) of CAFs that are present at varying levels in the different tumor lines. Telmisartan significantly altered the CAF content of tumors while also reducing CAF-mediated collagen deposition in the tumor microenvironment. We found that telmisartan also decreased tumor hypoxia and improved radiation response in our pre-clinical models, indicating that CAF subsets help to create hypoxia and contribute to radioresistance of solid tumors in an AT1R-dependent manner. Using a retrospective cohort of over 1,100 oropharyngeal cancer patients, we found that patients taking ARBs had dramatically improved therapeutic outcomes after radiation therapy, validating our pre-clinical data and supporting the further development and testing of ARBs as neoadjuvant therapies for patients with hypoxic tumors. Understanding how the solid tumor microenvironment influences cancer therapy is central to improving treatment outcome, and our work identifies CAFs as key contributors to the development of hypoxia in solid tumors. Repurposing clinically approved, anti-hypertensive ARBs represents a novel therapeutic strategy to inhibit CAF activity, modify the solid tumor microenvironment, reduce tumor hypoxia, and improve radiation response.
Citation Format: Brennan J. Wadsworth, Che-Min Lee, Ryan Urban, Sarah N. Hamilton, Kevin L. Bennewith. Angiotensin II receptor blockers modify the solid tumor microenvironment and improve radiation therapy response [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 PR-001.