Augmenting major histocompatibility complex class I expression by murine tumors in vivo enhances antitumor immunity induced by an active immunotherapy strategy. Academic Article Article uri icon

Overview

MeSH

  • Animals
  • CD8-Positive T-Lymphocytes
  • Cytotoxicity, Immunologic
  • Dose-Response Relationship, Immunologic
  • Drug Therapy, Combination
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • H-2 Antigens
  • Immunity, Cellular
  • Interferon-gamma
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Recombinant Proteins
  • T-Lymphocytes, Cytotoxic
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Up-Regulation

MeSH Major

  • Carcinoma, Lewis Lung
  • Genes, MHC Class I
  • Immunotherapy, Active
  • Lung Neoplasms

abstract

  • Tumors down-regulate major histocompatibility complex class I expression, escaping recognition by the cellular immune response. We hypothesized that augmentation of tumor cell class I expression by interferon-gamma would enhance the cellular antitumor immune response and cure rate of an active immunotherapy strategy. B16.F10 tumor cells were exposed to interferon-gamma in culture, and class I expression was quantified using flow cytometry. Syngeneic mice bearing established tumors were injected with interferon-gamma (5000 U, intraperitoneal), and class I expression was assessed using immunohistochemistry. Tumor-specific cytotoxic T lymphocytes were induced in mice by an intratumoral injection of AdCD40L (5 x 10(10) particles), an adenovirus gene transfer vector-based immunotherapy strategy previously demonstrated to augment cellular antitumor immunity. A conjugate-formation assay and the enzyme-linked immunospot assay were used to evaluate the binding and activation of cytotoxic T lymphocytes, respectively. Interferon-gamma was administered to tumor-bearing mice concomitantly with intratumoral AdCD40L. End points measured included the frequencies of cytotoxic T lymphocytes using the enzyme-linked immunospot assay, tumor size, and mouse survival. The role of class I expression was further evaluated by monoclonal antibody blockade in both in vitro and in vivo experiments. B16.F10 cells exposed to interferon-gamma expressed significantly more class I, both in vitro and in vivo, and were able to bind to and activate cytotoxic T lymphocytes more efficiently than untreated cells. Cytotoxic T-lymphocyte frequencies, tumor regression, and the cure rate induced by AdCD40L were augmented by the addition of a single dose of interferon-gamma in tumor-bearing mice. These in vitro and in vivo effects of interferon-gamma were attenuated by class I monoclonal antibody blockade. Up-regulation of class I expression using interferon-gamma enhances the cellular antitumor immune response and cure rate of AdCD40L, an active immunotherapy strategy. This approach may be useful for human tumors that lack class I expression.

publication date

  • February 2004

has subject area

  • Animals
  • CD8-Positive T-Lymphocytes
  • Carcinoma, Lewis Lung
  • Cytotoxicity, Immunologic
  • Dose-Response Relationship, Immunologic
  • Drug Therapy, Combination
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Genes, MHC Class I
  • H-2 Antigens
  • Immunity, Cellular
  • Immunotherapy, Active
  • Interferon-gamma
  • Lung Neoplasms
  • Lymphocyte Activation
  • Mice
  • Mice, Inbred C57BL
  • Models, Animal
  • Recombinant Proteins
  • T-Lymphocytes, Cytotoxic
  • Treatment Outcome
  • Tumor Cells, Cultured
  • Up-Regulation

Research

keywords

  • Comparative Study
  • Evaluation Studies
  • Journal Article

Identity

Language

  • eng

Digital Object Identifier (DOI)

  • 10.1016/j.jtcvs.2003.09.007

PubMed ID

  • 14762342

Additional Document Info

start page

  • 355

end page

  • 364

volume

  • 127

number

  • 2