Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma

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 DownesRonald M. Evans, James Michaelson, Cristina R. Ferrone, Yves Boucher, Rakesh K. Jain

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Abstract

Purpose: Angiotensin system inhibitors (ASI) can improve score–adjusted analysis also showed a longer median OS for prognosis in multiple cancer types, including pancreatic ductal chronic ASI users. In unresected patients, the beneficial effect of adenocarcinoma (PDAC). However, no study has examined the ASIs was significant in patients with locally advanced disease, but effect of ASIs alone or combined with adjuvant chemotherapy in not in metastatic patients. RNA-Seq analysis revealed in tumors of resected PDAC patients. ASI users (lisinopril) a normalized extracellular matrix, a reduced Experimental Design: We performed an analysis of the records expression of genes involved in PDAC progression (e.g., WNT of ASI users and nonuser patients with PDAC seen at Massachusetts and Notch signaling), and an increased expression of genes linked General Hospital (Boston, MA) between January 2006 and Decem-with the activity of T cells and antigen-presenting cells. Finally, ber 2010. To identify mechanisms of ASIs in PDAC, we performed chronic use of ASI was associated with a gene expression signature RNA sequencing (RNA-Seq) of resected primary lesions. that is predictive of survival in independent validation cohorts. Results: A total of 794 consecutive patients were included. In Conclusions: In patients with nonmetastatic PDAC, chronic ASI 299 resected patients, ASI users experienced longer overall survival use is associated with longer OS independently of chemotherapy. (OS) in both univariate (median OS, 36.3 vs. 19.3 months, P ¼ Our RNA-Seq analysis suggests that ASIs reduce the malignant 0.011) and adjusted multivariate [HR, 0.505; 95% confidence potential of cancer cells and stimulate the immune microenviron-interval (CI), 0.339–0.750; P ¼ 0.001] analyses.

Original languageEnglish
Pages (from-to)5959-5969
Number of pages11
JournalClinical Cancer Research
Volume23
Issue number19
DOIs
Publication statusPublished - 2017 Oct 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Liu, H., Naxerova, K., Pinter, M., Incio, J., Lee, H., Shigeta, K., Ho, W. W., Crain, J. A., Jacobson, A., Michelakos, T., Dias-Santos, D., Zanconato, A., Hong, T. S., Clark, J. W., Murphy, J. E., Ryan, D. P., Deshpande, V., Lillemoe, K. D., Castillo, C. F. D., ... Jain, R. K. (2017). Use of angiotensin system inhibitors is associated with immune activation and longer survival in nonmetastatic pancreatic ductal adenocarcinoma. Clinical Cancer Research, 23(19), 5959-5969. https://doi.org/10.1158/1078-0432.CCR-17-0256