Experimental Manipulation of Melanoma-Induced Immune Suppression

Funding:

Central Surgical Association

Principal Investigator:

Clifford Cho, MD

Project Summary:

Our laboratory effort is directed at measuring the influence of melanoma on physiologically relevant immune responses. We have recently established a highly sensitive and quantitative animal model that confirms the ability of melanoma to suppress the in vivo T cell response to de novo antigen. By taking advantage of the well-characterized immunological response to the murine pathogen lymphocytic choriomeningitis virus (LCMV), we have demonstrated that growing melanomas significantly suppress the ability of mice to expand LCMV-specific populations of effector T cells in response to infection. Furthermore, we have observed that the extent of this melanoma-induced immune suppression is directly proportional the extent of tumor burden. In effect, our model demonstrates that melanoma inhibits the ability of T cells to expand in response to physiological antigenic stimulation, thus providing an experimental system with which to dissect the mechanisms of melanoma-induced immune suppression.

This project will (1) determine if melanoma-induced suppression of T cell expansion is mediated at the level of antigen presentation or through direct T cell suppression, and will (2) delineate the influence of melanoma not only on the induction but also on the homeostatic maintenance of the immune response. We will then use our model to address questions of more immediate clinical relevance, specifically to (3) compare melanoma-induced suppression of immune responses to tumor-related versus tumor-unrelated antigens, and (4) test the influence of CTLA-4 blockade, an adjunct that has been incorporated into experimental immunotherapy trials for melanoma, on melanoma-induced immune suppression. As a result of this work, we wish to understand some of the biological mechanisms underlying melanoma-induced immune suppression, and hope to evaluate the efficacy of translational strategies to mitigate this clinically undesirable phenomenon.

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General Surgery University of Wisconsin Department of Surgery
First published: 07/15/02 Last updated: 11/24/09 webmaster@surgery.wisc.edu
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