Angiotensin-II-induced chronic hypertension reprograms the antitumor-immune-response in pancreatic ductal adenocarcinoma

Introduction: Chronic arterial hypertension (CAH) is one of the most prevalent medical conditions worldwide and plays a causal role in cardiovascular diseases. Cancer patients with CAH have inferior outcomes compared to non-hypertensive cancer patients, especially in pancreatic ductal adenocarcinoma (PDAC). Furthermore, retrospective analyses have shown that antihypertensive therapy targeting angiotensin signaling is associated with improved oncological outcomes compared to other anti-hypertensive treatments in cancer patients. Methods and Results: To investigate this relationship, we employed a syngeneic, orthotopic PDAC model in mice with chronic hypertension induced by subcutaneously implanted osmotic minipumps delivering angiotensin II. Using highly multiplexed spectral flow cytometry, we found that chronic angiotensin II administration re-wires the anti-tumor immune response, leading to an increased presence of myeloid cells, particularly Ly6C+ monocytes, and CD206+ macrophages. Blockage of the angiotensin II receptor type I (AT1) with losartan leads to a marked decrease in tumor growth and a reduction in MDSCs. This effect was observed only with the synchronous administration of angiotensin II and losartan, not with losartan alone, and was consistent across different PDAC treatment regimens. In addition, we observed a trend toward improved tumor vessel perfusion in hypertensive mice treated with losartan, indicating vascular repair. Additional findings suggest that inhibition of the angiotensin II receptor type 2 (AT2) and the Mas receptor (which physiologically counterbalance AT1 signaling) abrogated the beneficial effect of AT1 blockade with losartan, suggesting a role for AT2 and the Mas receptor in shaping the immune microenvironment. Conclusion: Overall, our findings show that CAH reprograms the tumor microenvironment in PDAC and that inhibition of angiotensin signaling reverses these changes. This may indicate that inhibition of angiotensin signaling in cancer patients with CAH may exert its beneficial effect by reprogramming the anti-tumor immune response.