Use of Angiotensin System Inhibitors Is Associated with Immune Activation and Longer Survival in Nonmetastatic Pancreatic Ductal Adenocarcinoma - PubMed (original) (raw)

. 2017 Oct 1;23(19):5959-5969.

doi: 10.1158/1078-0432.CCR-17-0256. Epub 2017 Jun 9.

Kamila Naxerova 1, Matthias Pinter 1, Joao Incio 1, Hang Lee 3, Kohei Shigeta 1, William W Ho 1 4, Jonathan A Crain 1, Alex Jacobson 5, Theodoros Michelakos 6, Daniella Dias-Santos 6, Andrea Zanconato 6, Theodore S Hong 7, Jeffrey W Clark 8, Janet E Murphy 8, David P Ryan 8, Vikram Deshpande 9, Keith D Lillemoe 6, Carlos Fernandez-Del Castillo 6, Michael Downes 10, Ronald M Evans 10, James Michaelson 5, Cristina R Ferrone 6, Yves Boucher 11, Rakesh K Jain 11

Affiliations

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

Hao Liu et al. Clin Cancer Res. 2017.

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.

©2017 American Association for Cancer Research.

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Conflict of interest statement

Conflict of Interest Disclosure statement: R.K.J. received consultant fees from Ophthotech, SPARC, SynDevRx and XTuit. R.K.J owns equity in Enlight, SPARC, SynDevRx and XTuit, and serves on the Board of Directors of XTuit and Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, Tekla Healthcare Opportunities Fund and Tekla World Healthcare Fund. Y.B. received consultant fees from XTuit. M.P. received travel grants and speaker fees from Bayer. No reagents or funding from these companies were used in these studies. R.K.J only had access to de-identified data.

Figures

Figure 1

Figure 1. Unadjusted Kaplan Meier curves for overall survival in metastatic (A), locally advanced (B) and resected (C) patients. HR = Hazards ratio

Figure 2

Figure 2

A: Number of GO, BIOCARTA, KEGG, PID, and REACTOME gene sets that are significantly changed (FDR<0.05) in our GSEA analysis, grouped by biological function. (Complete GSEA results are shown in Supplementary Table 9). Gene Set Enrichment Analysis (GSEA) of human PDAC comparing ACEi treated tumors vs. control tumors. B: Decrease in the activity of integrin beta 3, NOTCH, WNT and the cell cycle. C: Increase in oxidative phosphorylation, improvement in lipid metabolism, PPAR signaling, and adaptive immune response. D: Increase in cytotoxic activities, immuno-synapse and antigen presentation pathways (Detailed enrichment score in Supplementary Table 11).

Figure 3

Figure 3

Kaplan Meier analysis on ASI down regulated gene pathway and overall survival. ASI low pathway expression level: 1 = low, 2 = med, 3 = high. A: UNC dataset. B: TCGA dataset, overall survival. UNC Dataset overall Kaplan Meier analysis p=0.017, HR =0.513, 95% CI = 0.292 - 0.900. TCGA Dataset overall Kaplan Meier analysis p=0.002, HR =0.422, 95% CI = 0.248 - 0.718.

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