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

Abstract

Purpose: Angiotensin system inhibitors (ASI) 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 nonuser patients with PDAC seen at Massachusetts General Hospital (Boston, MA) between January 2006 and December 2010. To identify mechanisms of ASIs in PDAC, we performed RNA sequencing (RNA-Seq) of resected primary lesions.Results: A total of 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% confidence interval (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 that is predictive of survival in independent validation cohorts.Conclusions: In patients with nonmetastatic PDAC, chronic ASI use is associated with longer OS independently of chemotherapy. Our RNA-Seq analysis suggests that ASIs reduce the malignant potential of cancer cells and stimulate the immune microenvironment in primary PDAC. Clin Cancer Res; 23(19); 5959-69. ©2017 AACR.

• Authors: Hao Liu, Kamila Naxerova, Matthias Pinter, Joao Incio, Hang Lee, Kohei Shigeta, William W Ho, Jonathan A Crain, Alex Jacobson, Theodoros Michelakos, Daniella Dias-Santos, Andrea Zanconato, Theodore S Hong, Jeffrey W Clark, Janet E Murphy, David P Ryan, Vikram Deshpande, Keith D Lillemoe, Carlos Fernandez-Del Castillo, Michael Downes, Ronald M Evans, James Michaelson, Cristina R Ferrone, Yves Boucher, Rakesh K Jain
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 23 Issue 19 Pg. 5959-5969 (Oct 01 2017) ISSN: 1557-3265 [Electronic] United States
• PMID: 28600474 (Publication Type: Journal Article)
• Copyright: ©2017 American Association for Cancer Research.

Chemical References

• Angiotensins
• Biomarkers, Tumor
• Neoplasm Proteins

Topics

• Adenocarcinoma (drug therapy, genetics, immunology, pathology)
• Angiotensins (antagonists & inhibitors, immunology)
• Antigen-Presenting Cells (drug effects, immunology)
• Biomarkers, Tumor (genetics)
• Carcinoma, Pancreatic Ductal (drug therapy, genetics, immunology, pathology)
• Disease-Free Survival
• Female
• Gene Expression Regulation, Neoplastic (drug effects, immunology)
• Humans
• Kaplan-Meier Estimate
• Male
• Middle Aged
• Neoplasm Proteins (genetics, immunology)
• Prognosis