Localized expression of GITR-L in the tumor microenvironment promotes CD8+ T cell dependent anti-tumor immunity

  • John S. Cho
  • Jeffrey V. Hsu
  • Sherie L. Morrison
Original Article

Abstract

The systemic administration of an agonist antibody against glucocorticoid-induced tumor necrosis factor receptor related (GITR) protein has been shown to be effective in overcoming immune tolerance and promoting tumor rejection in a variety of murine tumor models. However, little is known regarding the functional consequence of ligation of GITR with its natural ligand (GITR-L) in the context of regulatory T cell (Treg) suppression in vivo. To determine the mechanism of GITR-L action in vivo, we generated a panel of tumor cell clones that express varying levels of GITR-L. The ectopic expression of GITR-L on the tumor cell surface was sufficient to enhance anti-tumor immunity and delay tumor growth in syngeneic BALB/c mice. Within the range examined, the extent of anti-tumor activity in vivo did not correlate with the level of GITR-L expression, as all clones tested exhibited a similar delay in tumor growth. The localized expression of GITR-L on tumor cells led to a significant increase in CD8+ T cell infiltration compared to the levels seen in control tumors. The increased proportion of CD8+ T cells was only observed locally at the tumor site and was not seen in the tumor draining lymph node. Depletion studies showed that CD8+ T cells, but not CD4+ T cells, were required for GITR-L mediated protection against tumor growth. These studies demonstrate that signaling between GITR-L and GITR in the tumor microenvironment promotes the infiltration of CD8+ T cells, which are essential for controlling tumor growth.

Keywords

Rodent T cells T cells cytotoxic Costimulation Tumor immunity 

Abbreviations

GITR

Glucocorticoid-induced TNF receptor related

GITR-L

GITR ligand

Tregs

Regulatory T cells

ECD

Extracellular domain

Supplementary material

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Copyright information

© Springer-Verlag 2008

Authors and Affiliations

  • John S. Cho
    • 1
  • Jeffrey V. Hsu
    • 1
  • Sherie L. Morrison
    • 1
  1. 1.Department of Microbiology, Immunology and Molecular GeneticsUniversity of California Los AngelesLos AngelesUSA

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