Cancer Immunology, Immunotherapy

, 58:1057

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

Authors

  • John S. Cho
    • Department of Microbiology, Immunology and Molecular GeneticsUniversity of California Los Angeles
  • Jeffrey V. Hsu
    • Department of Microbiology, Immunology and Molecular GeneticsUniversity of California Los Angeles
    • Department of Microbiology, Immunology and Molecular GeneticsUniversity of California Los Angeles
Original Article

DOI: 10.1007/s00262-008-0622-2

Cite this article as:
Cho, J.S., Hsu, J.V. & Morrison, S.L. Cancer Immunol Immunother (2009) 58: 1057. doi:10.1007/s00262-008-0622-2

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

RodentT cellsT cells cytotoxicCostimulationTumor 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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Supplemental Figure 4 (EPS 1229 kb)

Copyright information

© Springer-Verlag 2008