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Copyright ©The Author(s) 2018. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. May 28, 2018; 24(20): 2137-2151
Published online May 28, 2018. doi: 10.3748/wjg.v24.i20.2137
Immune therapies in pancreatic ductal adenocarcinoma: Where are we now?
Marc Hilmi, Laurent Bartholin, Cindy Neuzillet
Marc Hilmi, Cindy Neuzillet, Service d’Oncologie Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, Créteil 94010, France
Laurent Bartholin, Université de Lyon, Université Claude Bernard Lyon 1, Inserm U1052, CNRS 5286, Centre Léon Bérard, Centre de Recherche en Cancérologie de Lyon, Lyon 69008, France
Author contributions: All authors contributed equal to this paper including conception and design of the study, literature review and analysis, drafting and critical revision and editing, and approval of the final version.
Conflict-of-interest statement: Neuzillet C reports non-financial support from OSE Immunotherapeutics; Hilmi M and Bartholin L have no potential conflicts of interest relevant to this article were reported.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Cindy Neuzillet, MD, MSc, Service d’Oncologie Médicale, Hôpital Henri Mondor, Assistance Publique-Hôpitaux de Paris, Université Paris Est Créteil, 51 Avenue du Maréchal de Lattre de Tassigny, Créteil 94010, France. cindy.neuzillet@gmail.com
Telephone: +33-682-550492
Received: March 28, 2018
Peer-review started: March 29, 2018
First decision: April 27, 2018
Revised: May 5, 2018
Accepted: May 18, 2018
Article in press: May 18, 2018
Published online: May 28, 2018
Processing time: 60 Days and 14 Hours
Abstract

Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, mostly due to its resistance to treatment. Of these, checkpoint inhibitors (CPI) are inefficient when used as monotherapy, except in the case of a rare subset of tumors harboring microsatellite instability (< 2%). This inefficacy mainly resides in the low immunogenicity and non-inflamed phenotype of PDAC. The abundant stroma generates a hypoxic microenvironment and drives the recruitment of immunosuppressive cells through cancer-associated-fibroblast activation and transforming growth factor β secretion. Several strategies have recently been developed to overcome this immunosuppressive microenvironment. Combination therapies involving CPI aim at increasing tumor immunogenicity and promoting the recruitment and activation of effector T cells. Ongoing studies are therefore exploring the association of CPI with vaccines, oncolytic viruses, MEK inhibitors, cytokine inhibitors, and hypoxia- and stroma-targeting agents. Adoptive T-cell transfer is also under investigation. Moreover, translational studies on tumor tissue and blood, prior to and during treatment may lead to the identification of biomarkers with predictive value for both clinical outcome and response to immunotherapy.

Keywords: Drug therapy combination; Immunology; Hypoxia; Checkpoint inhibitor; Inflammation; Pancreatic cancer; Tumor-infiltrating lymphocyte; Transforming growth factor β; Tumor microenvironment

Core tip: Checkpoint inhibitors (CPI) and other immune therapies remain inefficient when used as single agents in pancreatic ductal adenocarcinoma (PDAC). Here, we present an overview of the biological mechanisms underlying these failures and the lessons learned, giving a rationale for innovative combination therapies. In particular, the latest ongoing studies are attempting to overcome the immunosuppressive microenvironment, the basis of resistance to CPI in PDAC.