Journal
CANCER IMMUNOLOGY IMMUNOTHERAPY
Volume 58, Issue 7, Pages 1057-1069Publisher
SPRINGER
DOI: 10.1007/s00262-008-0622-2
Keywords
Rodent; T cells; T cells cytotoxic; Costimulation; Tumor immunity
Categories
Funding
- National Institutes of Health [CA-16042, AI-28697]
- JCCC
- UCLA AIDS Institute
- David Geffen School of Medicine at UCLA
- UCLA Chancellor's Office
- NIH Tumor Immunology training [5 T32 CA009120: 32]
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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.
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