Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma

Abstract

Purpose Angiotensin system inhibitors (ASIs) can improve prognosis in multiple cancer types, including pancreatic ductal adenocarcinoma (PDAC). However, no study has examined the effect of ASIs alone or combined with adjuvant chemotherapy in resected PDAC patients. Experimental Design We performed an analysis of the records of ASI users and non-user patients with PDAC seen at Massachusetts General Hospital between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA-Seq of resected primary lesions. Results 794 consecutive patients were included. In 299 resected patients, ASI-users experienced longer overall survival (OS) in both univariate (median OS: 36.3 vs. 19.3 months, p=0.011) and adjusted multivariate (HR, 0.505; 95%CI, 0.339 - 0.750; p=0.001) analyses. Propensity score adjusted analysis also showed a longer median OS for chronic ASI-users. In unresected patients, the beneficial effect of ASIs was significant in patients with locally advanced disease, but not in metastatic patients. RNA-Seq analysis revealed in tumors of ASI-users (lisinopril) a normalized extracellular matrix, a reduced expression of genes involved in PDAC progression (e.g. WNT and Notch signaling) and an increased expression of genes linked with the activity of T cells and antigen-presenting cells. Finally, chronic use of ASI was associated with a gene expression signature which is predictive of survival in independent validation cohorts. Conclusions In patients with non-metastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASI reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC.

Enhancing cancer immunotherapy using antiangiogenics: opportunities and challenges

“…We have also shown that widely prescribed ARBs can normalize the stroma and decompress blood vessels, thereby improving the outcome of chemotherapy 94 . Moreover, RNA sequencing analyses of tumour specimens from patients with pancreatic ductal adenocarcinoma have revealed that ARBs can activate both the innate and adaptive immune system 112 . Thus, the testing of combinations of ARBs with antiangiogenic agents 113 and immune-checkpoint inhibitors 95 is warranted.…”

Engineering and physical sciences in oncology: challenges and opportunities

“…Treatment with losartan, a clinically approved angiotensin II receptor antagonist shown to reduce 6 , also reduced solid stresses and pancreatic tumour progression in mice 43 . Moreover, angiotensin system inhibitors including losartan can also activate both innate and adaptive immune pathways in patients with PDAC 44 . The feasibility of using losartan to treat patients with pancreatic cancer was demonstrated in a phase II clinical trial (NCT01821729) 45,46 .…”

Upregulation of ASPM, BUB1B and SPDL1 in tumor tissues predicts poor survival in patients with pancreatic ductal adenocarcinoma

“…Previous studies have demonstrated that the interactions between ligands and integrins, such as αvβ6, could affect the proliferation, invasion, metastasis and angiogenesis of PDAC cells (5,25,26). Furthermore, hormone inhibitors, such as angiotensin system inhibitors were applied to improve the prognosis of PDAC (27). KEGG pathway analysis demonstrated that the upregulated genes were predominantly involved in 'ECM-receptor interaction' and the 'cGMP-PKG signaling pathway', which has been identified as a key signaling pathway in different types of cancer, including bladder cancer (28).…”