Established tumors create a condition of immunologic unresponsiveness toward their own antigens (functional tolerance) which constitutes a major barrier to successful immunotherapy of cancer. New therapeutic strategies are needed that specifically target this important but poorly understood problem. One mechanism by which antigen-presenting cells (APCs) can inhibit T cell responses, and hence create tolerance, is through tryptophan catabolism via the enzyme indoleamine 2,3-dioxygenase (IDO). Malignant melanoma and other human tumors recruit large numbers of IDO-expressing APCs into tumor-draining lymph nodes. The applicants hypothesize that presentation of tumor-derived antigens by IDO expressing APCs contributes to the pathologic tolerance toward tumor antigens found in malignancy.
In Aim #1 the applicants will test the hypothesis that IDO-dependent mechanisms block the development of protective immune responses at the time of prophylactic immunization with tumor antigens. This will be accomplished by administration of the IDO-inhibitor drug 1-methyl-[D]-tryptophan to mice receiving immunization with irradiated B16F10 tumor cells or defined antigenic peptides, and by the use of antigen-pulsed dendritic cells from IDO-transgenic and IDO-knockout mice.
In Aim #2 the applicants will test the hypothesis that T cells encountering antigen in tumor-draining lymph nodes are forced into IDO-mediated cell-cycle arrest in mid-G1, with consequent failure of clonal expansion and inability to develop CTL activity. Using an established-tumor model, the applicants will combine 1-methyl-[D]-tryptophan with vaccination to test the hypothesis that IDO-dependent mechanisms inhibit T cell responses to therapeutic immunization. The proposed studies will provide insight into the role of IDO as a tolerogenic mechanism in the pathogenesis of malignancy, and will test the efficacy of 1-methyl-[D]-tryptophan as a therapeutic intervention designed to block this pathway.
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