) We have recently discovered a novel mechanism for the down-regulation of expression of a tumor-associated antigen. Such down-regulation, which we call """"""""antigen silencing"""""""", exemplifies one route by which a tumor can escape immune destruction in the presence of tumor specific, cytotoxic T-cells. This Phase I project has as one of its goals the isolation and characterization of the tumor-secreted protein that induces """"""""antigen-silencing."""""""" Isolation of this protein factor represents the first step toward our objective of developing therapeutics whose use will result in the maintenance of, or reversal of the loss of, antigens recognized by cytotoxic T lymphocytes. Such therapeutics would restore tumor susceptibility to immune-mediated destruction. Determination of the sequence of the factor, in addition to providing clues to its mechanism of action (and therefore a roadmap to future therapeutic approaches), will allow us to produce cDNA for it, and recombinant protein for antibody and other reagent development. Factor-specific antibodies will allow us to evaluate patient samples for the in vivo appearance of the factor, and to demonstrate that reversal of antigen down-regulation can be accomplished. Phase II will develop drug screens for compounds that up-regulate antigen expression.
We propose the development of a therapy which will prevent the escape of tumors from immune destruction. Although preliminary evidence has been limited to a single tumor type, future implementation on a variety of tumors could make the proposed strategy a part of general cancer therapy designed to enhance the host's ability to control tumor growth.
| Haggerty, Timothy J; Dunn, Ian S; Rose, Lenora B et al. (2012) A screening assay to identify agents that enhance T-cell recognition of human melanomas. Assay Drug Dev Technol 10:187-201 |
| Haggerty, Timothy J; Dunn, Ian S; Rose, Lenora B et al. (2011) Topoisomerase inhibitors modulate expression of melanocytic antigens and enhance T cell recognition of tumor cells. Cancer Immunol Immunother 60:133-44 |
| Dunn, Ian S; Haggerty, Timothy J; Kono, Michihiro et al. (2007) Enhancement of human melanoma antigen expression by IFN-beta. J Immunol 179:2134-42 |
| Kono, Michihiro; Dunn, Ian S; Durda, Paul J et al. (2006) Role of the mitogen-activated protein kinase signaling pathway in the regulation of human melanocytic antigen expression. Mol Cancer Res 4:779-92 |
| Durda, Paul J; Dunn, Ian S; Rose, Lenora Boyle et al. (2003) Induction of ""antigen silencing"" in melanomas by oncostatin M: down-modulation of melanocyte antigen expression. Mol Cancer Res 1:411-9 |
