Angiotensin receptor blocker attacks armored and cold tumors and boosts immune checkpoint blockade

Abstract

Background Immune checkpoint blockade (ICB) has made remarkable achievements, but newly identified armored and cold tumors cannot respond to ICB therapy. The high prevalence of concomitant medications has huge impact on immunotherapeutic responses, but the clinical effects on the therapeutic outcome of armored and cold tumors are still unclear.Methods In this research, using large-scale transcriptomics datasets, the expression and potential biological functions of angiotensin II receptor 1 (AGTR1), the target of angiotensin receptor blocker (ARB), were investigated. Next, the roles of ARB in tumor cells and tumor microenvironment cells were defined by a series of in vitro and in vivo assays. In addition, the clinical impacts of ARB on ICB therapy were assessed by multicenter cohorts and meta-analysis.Results AGTR1 was overexpressed in armored and cold tumors and associated with poor response to ICB therapy. ARB, the inhibitor for AGTR1, only suppressed the aggressiveness of tumor cells with high AGTR1 expression, which accounted for a very small proportion. Further analysis revealed that AGTR1 was always highly expressed in cancer-associated fibroblasts (CAFs) and ARB inhibited type I collagen expression in CAFs by suppressing the RhoA-YAP axis. Moreover, ARB could also drastically reverse the phenotype of armored and cold to soft and hot in vivo, leading to a higher response to ICB therapy. In addition, both our in-house cohorts and meta-analysis further supported the idea that ARB can significantly enhance ICB efficacy.Conclusion Overall, we identify AGTR1 as a novel target in armored and cold tumors and demonstrate the improved therapeutic efficacy of ICB in combination with ARB. These findings could provide novel clinical insight into how to treat patients with refractory armored and cold tumors.