Abstract B016: Targeting the angiotensin receptor in cancer-associated fibroblasts improves tumour perfusion, oxygenation, and radiotherapy response
Authors: Lee Che-Min , Wadsworth Brennan J. , Cederberg Rachel A. , Li Zi Han , Thomas Kiersten N. , Clark Meredith , Shi Rocky , Hall Michael , Telkar Nikita , Urban Ryan , Lam Wan L. , Hamilton Sarah N. , Bennewith Kevin L. 
Published: January 2025

Abstract
The solid tumor microenvironment is a key determinant of successful cancer therapy, with hypoxic tumor cells known to contribute to poor therapeutic outcome after radiation therapy, chemotherapy, and surgery. Several targeted therapies have been developed against hypoxic tumor cells that have shown promise in combination with radiation therapy in pre-clinical models and early phase clinical trials, although the difficulty inherent in targeting hypoxic cells has limited the overall efficacy of this approach. Our recent data suggest that hypoxia can develop in solid tumors due to the activity of sub-populations of cancer-associated fibroblasts (CAFs), and that therapeutically targeting CAF activation can restrict the development of tumor hypoxia and prime tumors to respond to radiation therapy. Angiotensin II type 1 receptor (AT1R) blockers (ARBs) are anti-hypertensive agents that inhibit the activity of the signaling peptide angiotensin II derived from the renin-angiotensin system. ARBs can also exhibit anti-fibrotic activity by blocking the AT1R expressed on myofibroblasts in various tissues. We recently found that the ARB telmisartan inhibits the deposition of collagen I in solid tumors, increasing net tumor perfusion and stabilizing microregional tumor blood flow. Collagen I can be produced by CAFs, although recent clinical data have identified multiple, functionally-diverse CAF subsets in breast and ovarian tumors. To understand how ARBs affect the solid tumor microenvironment, we wanted to determine how the ARB telmisartan influences the activity of CAF subsets and whether telmisartan-associated changes in perfusion impact hypoxia and radiation response in solid tumors. We identified several murine CAF subsets that could be discriminated by cell surface marker expression across a panel of seven tumor xenograft lines. Using single cell RNAseq of cells isolated from tumors with or without ARB treatment, we found that telmisartan altered the transcriptome of CAF subsets and inhibited CAF activation. In tumors containing myofibroblast-like CAFs, telmisartan decreased collagen deposition and eliminated ‘acute’ hypoxia that can be caused by unstable microregional perfusion. Telmisartan-treated tumors also had improved response to ionizing radiation therapy. Taken together, our data indicate that CAFs contribute to tumor hypoxia and radiation resistance of solid tumors in an AT1R-dependent manner. Using a retrospective cohort of over 1,100 oropharyngeal cancer patients, we also found that patients taking ARBs for hypertension had dramatically improved therapeutic outcomes after radiation therapy. Our work indicates that CAFs contribute to the development of hypoxia in solid tumors and suggests that angiotensin receptor blockers represent a novel targeted therapy to inhibit CAF activity, modify the solid tumor microenvironment, reduce tumor hypoxia, and improve radiation response.
Citation Format: Che-Min Lee, Brennan J. Wadsworth, Rachel A. Cederberg, Zi Han Li, Kiersten N. Thomas, Meredith Clark, Rocky Shi, Michael Hall, Nikita Telkar, Ryan Urban, Wan L. Lam, Sarah N. Hamilton, Kevin L. Bennewith. Targeting the angiotensin receptor in cancer-associated fibroblasts improves tumour perfusion, oxygenation, and radiotherapy response. [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Translating Targeted Therapies in Combination with Radiotherapy; 2025 Jan 26-29; San Diego, CA. Philadelphia (PA): AACR; Clin Cancer Res 2025;31(2_Suppl):Abstract nr B016.