Optimization of Melanoma Vaccines with T-Helper Epitopes

University Of Pittsburgh At Pittsburgh, Pittsburgh PA

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Abstract

DESCRIPTION (provided by applicant): CD4+T cells play a critical role in the induction and maintenance of anti-tumor responses. In order to develop and optimize immunotherapeutic approaches to stimulate human tumor antigen (TA)-specific CD4+ T cells in vivo, we have previously identified a number of promiscuous MHC class II-restricted epitopes from cancer- germline antigens (CGAs), melanocyte-lineage antigens (MDAs) and overexpressed or universal antigens. We have shown that these epitopes stimulate spontaneous circulating TA-specific CD4+ T cells in peripheral blood lymphocytes (PBLs) of patients with advanced melanoma. Most recently, we have shown that TA-specific CD4+ T cells were either T helper or regulatory T cells (T regs). The goal of this proposal is to expand the functional studies of TA-specific regs isolated from patients with advanced melanoma. This research proposal stems from novel findings that be can be stated as follows: 1) MHC class II epitopes stimulate not only spontaneous Foxp3- T-helper and Foxp3+ T regs but also Foxp3+ T helper and Foxp3- T regs, questioning the reliability of Foxp3 as a marker of T regs in humans; 2) in contrast to naturally-occurring CD4+CD25+T regs, TA-specific T regs inhibit TA cross-presentation by DCs and cross-priming of TA-specific CD8+ T cells; 3) TA- specific T regs act on autologous B cells to inhibit IgG antibody production and stimulate IL-10 production; 4) Immature monocyte-derived DCs (iDCs) generated in an immunosuppressive milieu (IL-10 and TGF-2) can be activated by tumor antigen/antibody immune complexes (TA/Ab IC), promoting TA cross-presentation to CD8+ T cells and CD4+ T-helper functions. Collectively, the data generated in this proposal will develop the knowledge required for the induction of potent TA-specific T-helper responses in vivo in patients with advanced melanoma. They will provide a better understanding of the mechanisms by which TA-specific T regs inhibit cross-presentation/cross-priming by DCs and B cell antibody production. Therefore, they will contribute to the development of strategies aimed at expanding immune responses integrating TA-specific T helper cells, TA- specific CD8+ T cells and antibody responses in patients with melanoma.