Phenotypic T cell exhaustion in a murine model of bacterial infection in the setting of pre-existing malignancy

PLoS One. 2014 May 5;9(5):e93523. doi: 10.1371/journal.pone.0093523. eCollection 2014.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Adenocarcinoma / immunology*
  • Adenocarcinoma / pathology
  • Animals
  • Antigens, CD / immunology
  • CD4-Positive T-Lymphocytes / immunology*
  • CD4-Positive T-Lymphocytes / pathology
  • CD8-Positive T-Lymphocytes / immunology*
  • CD8-Positive T-Lymphocytes / pathology
  • Interferon-gamma / immunology
  • Interleukin-2 / immunology
  • Listeria monocytogenes / immunology*
  • Listeriosis / immunology*
  • Listeriosis / pathology
  • Male
  • Mice
  • Mice, Transgenic
  • Pancreatic Neoplasms / immunology*
  • Pancreatic Neoplasms / pathology
  • Programmed Cell Death 1 Receptor / immunology
  • Receptors, Immunologic / immunology
  • Signaling Lymphocytic Activation Molecule Family

Substances

  • Antigens, CD
  • BTLA protein, mouse
  • Cd244a protein, mouse
  • Interleukin-2
  • Pdcd1 protein, mouse
  • Programmed Cell Death 1 Receptor
  • Receptors, Immunologic
  • Signaling Lymphocytic Activation Molecule Family
  • Interferon-gamma