Phenotypic T Cell Exhaustion in a Murine Model of Bacterial Infection in the Setting of Pre-Existing Malignancy

• Type of Material: Article
• Authors: Rohit Mittal, Emory University; Maylene Wagener, Emory University; Elise R. Breed, Emory University; Zhe Liang, Emory University; Benyam P. Yoseph, Emory University; Eileen Burd, Emory University; Alton B Farris III, Emory University; Craig Coopersmith, Emory University; Mandy L Ford, Emory University
• Language: English
• Date: 2014
• Publisher: Public Library of Science
• Publication Version: Final Published Version
• Copyright Statement: © 2014 Mittal et al
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0093523
• Title of Journal or Parent Work: PLoS ONE
• ISSN: 1932-6203
• Volume: 9
• Issue: 5
• Start Page: e93523
• End Page: e93523
• Grant/Funding Information: This research was supported by the United States National Institutes of Health General Medical Sciences: T32GM095442 (CMC), R01GM104323 (CMC), R01GM072808 (CMC and MLF), and R01AI104699 (MLF). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
• Research Categories: Health Sciences, General; Health Sciences, Pathology

Abstract

While much of cancer immunology research has focused on anti-tumor immunity both systemically and within the tumor microenvironment, little is known about the impact of pre-existing malignancy on pathogen-specific immune responses. Here, we sought to characterize the antigen-specific CD8+ T cell response following a bacterial infection in the setting of pre-existing pancreatic adenocarcinoma. Mice with established subcutaneous pancreatic adenocarcinomas were infected with Listeria monocytogenes, and antigen-specific CD8+ T cell responses were compared to those in control mice without cancer. While the kinetics and magnitude of antigen-specific CD8+ T cell expansion and accumulation was comparable between the cancer and non-cancer groups, bacterial antigen-specific CD8+ T cells and total CD4+ and CD8+ T cells in cancer mice exhibited increased expression of the coinhibitory receptors BTLA, PD-1, and 2B4. Furthermore, increased inhibitory receptor expression was associated with reduced IFN-γ and increased IL-2 production by bacterial antigen-specific CD8+ T cells in the cancer group. Taken together, these data suggest that cancer's immune suppressive effects are not limited to the tumor microenvironment, but that pre-existing malignancy induces phenotypic exhaustion in T cells by increasing expression of coinhibitory receptors and may impair pathogen-specific CD8+ T cell functionality and differentiation.