Relationship of angiotensin II receptor blocker (ARB) to the effectiveness of immune checkpoint blockade (ICB) in non-small-cell lung cancer (NSCLC) and inhibition of angiotensin II/AGTR1 signaling in fibroblasts to reduce collagen deposition in the tumor microenvironment (TME).

Abstract

e14618 Background: Immune checkpoint blockade (ICB) has achieved remarkable success. However, not all patients with advanced tumors respond to ICB. Remodeling of the tumor microenvironment (TME) has emerged as a strategy to facilitate the development of cancer therapies. As the most notable features of TME, immune cells and collagens play a significant role in influencing anti-tumor immunity, with collagen deposition is the most significant physical barrier that hinders immune cell infiltration. Cancer patients are often prescribed multiple medications to address pre-existing comorbidities or side effects from anti-tumor therapy. Given the high prevalence of concurrent medications and the potential for interactions between them and ICB, we identified that the angiotensin II receptor 1 (AGTR1) was positively expressed in CAFs and AGTR1 inhibitor angiotensin receptor blocker (ARB) suppressed the expression of type I collagen and promote immune infiltration. Methods: Retrospective clinical study: An in-house cohort was a multi-center cohort and included 270 patients with non-small-cell lung cancer (NSCLC) receiving ICB therapy from 2020 to 2021 from The Affiliated Wuxi People's Hospital of Nanjing Medical University and The First Affiliated Hospital of Nanjing Medical University. Meta-analysis: 4 studies involving 1,268 participants in total and an in-house cohort with 270 participants were included. We performed an additional meta-analysis on the association between the use of ARBs in cancer patients receiving ICB therapy. Animal models: Xenograft tumor models were randomly divided into two groups, including control and Losartan-treated groups, and mouse cancer models were randomly divided into three groups at the first round and four groups at the second round. Three groups included control, Losartan-treated, and Losartan-treated & CD8-deleted groups, and four groups included control, Losartan-treated, anti-PD-1-treated, and Losartan & anti-PD-1-treated groups. Results: Patients with NSCLC who received ARBs showed improved overall survival and response to immunotherapy compared to those who did not receive ARBs. Losartan, a representative drug of the ARB class, significantly increased collagen deposition in mice tumors, elevated levels of immune cell infiltration, and sensitized anti-PD-1 therapy. Conclusions: We reported that Losartan shaped an inflamed TME by inhibiting collagen I expression of CAFs and enhanced anti-PD-1 immunotherapy in the mouse tumor model. We recommend that ARB should be selected as much as possible for patients receiving ICB therapy and requiring antihypertensive treatment.