Radiation delivered to the whole body or locally is immunomodulatory. Multiple arms of the immune system can be affected. A better mechanistic understanding of the subtleties of the interactions is a prerequisite if cancer immunotherapy is to be effectively combined with radiation therapy. This proposal focuses on radiation effects on dendritic cells (DC) functioning to process and present the human melanoma antigen MART-1 to cytotoxic T lymphocytes (CTL). Two pathways of antigen processing by DC have been identified. The endogenous pathway involves proteasome degradation, which is compromised by radiation. Irradiated DC is less able to generate protective immunity utilizing this pathway. In contrast, under similar conditions, presentation of an exogenous MART peptide antigen by DC is enhanced by radiation and by proteasome inhibition. It is hypothesized that this is due to alterations in stability of peptide or of MHC-peptide complexes on the surface of the DC. This proposal aims to study the effects of radiation on the endogenous and exogenous pathways of antigen presentation and the impact maturation status and proteasome composition of the DC will have on the responses. These basic mechanistic studies will give insight as to how to devise novel strategies to convert tumor death during radiation therapy into the generation of immunity that would assist in gaining local tumor control and inhibit the development of micrometastatic disease. ? ?
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