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

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.

• Authors: John S Cho, Jeffrey V Hsu, Sherie L Morrison
• Journal: Cancer immunology, immunotherapy : CII (Cancer Immunol Immunother) Vol. 58 Issue 7 Pg. 1057-69 (Jul 2009) ISSN: 1432-0851 [Electronic] Germany
• PMID: 19018533 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Glucocorticoid-Induced TNFR-Related Protein
• Receptors, Nerve Growth Factor
• Receptors, Tumor Necrosis Factor
• Tnfrsf18 protein, mouse
• Tnfsf18 protein, mouse
• Tumor Necrosis Factors

Topics

• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism)
• CD8-Positive T-Lymphocytes (immunology, metabolism)
• Cell Line, Tumor
• Colonic Neoplasms (immunology)
• Female
• Genetic Vectors
• Glucocorticoid-Induced TNFR-Related Protein
• Immune Tolerance
• Mice
• Mice, Inbred BALB C
• Receptors, Nerve Growth Factor (immunology, metabolism)
• Receptors, Tumor Necrosis Factor (immunology, metabolism)
• T-Lymphocytes, Regulatory (immunology, metabolism)
• Transfection
• Tumor Necrosis Factors (immunology, metabolism)