title: Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy.
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.
authors.affiliation: Department of Surgery and Emory Center for Critical Care, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Rohit
authors.initials: R
authors.lastname: Mittal
authors.affiliation: Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Maylene
authors.initials: M
authors.lastname: Wagener
authors.affiliation: Department of Surgery and Emory Center for Critical Care, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Elise R
authors.initials: ER
authors.lastname: Breed
authors.affiliation: Department of Surgery and Emory Center for Critical Care, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Zhe
authors.initials: Z
authors.lastname: Liang
authors.affiliation: Department of Surgery and Emory Center for Critical Care, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Benyam P
authors.initials: BP
authors.lastname: Yoseph
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Eileen M
authors.initials: EM
authors.lastname: Burd
authors.affiliation: Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Alton B
authors.initials: AB
authors.lastname: Farris
authors.affiliation: Department of Surgery and Emory Center for Critical Care, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Craig M
authors.initials: CM
authors.lastname: Coopersmith
authors.affiliation: Department of Surgery and Emory Transplant Center, Emory University School of Medicine, Atlanta, Georgia, United States of America.
authors.forename: Mandy L
authors.initials: ML
authors.lastname: Ford
mesh_terms: D000230:Adenocarcinoma / Q000276:immunology* / Q000473:pathology; D000818:Animals; D015703:Antigens, CD / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology* / Q000473:pathology; D007371:Interferon-gamma / Q000276:immunology; D007376:Interleukin-2 / Q000276:immunology; D008089:Listeria monocytogenes / Q000276:immunology*; D008088:Listeriosis / Q000276:immunology* / Q000473:pathology; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010190:Pancreatic Neoplasms / Q000276:immunology* / Q000473:pathology; D061026:Programmed Cell Death 1 Receptor / Q000276:immunology; D011971:Receptors, Immunologic / Q000276:immunology; D000071176:Signaling Lymphocytic Activation Molecule Family
chemical_list: D015703:Antigens, CD; C488868:BTLA protein, mouse; C490007:Cd244a protein, mouse; D007376:Interleukin-2; C491383:Pdcd1 protein, mouse; D061026:Programmed Cell Death 1 Receptor; D011971:Receptors, Immunologic; D000071176:Signaling Lymphocytic Activation Molecule Family; D007371:Interferon-gamma