Novel Combinatorial Immunotherapy for Melanoma
Technical Report,30 Sep 2014,29 Sep 2015
Medical College of Wisconsin Milwaukee
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Our research has discovered a novel immune-suppressive ligand protein called V-domain Immunoglobulin Suppressor of T cell Activation VISTA. By directly suppressing T cell-mediated adaptive immune response, VISTA critically impairs anti-tumor immune responses. VISTA monoclonal antibody-mediated blockade synergizes with a peptide vaccine using TLR agonists as adjuvants to potently reject established tumor. Based on these preliminary data, three specific aims are proposed to address the interplay between VISTA pathway and TLR signaling in multiple cell types, namely effector T cells, Foxp3CD4 regulatory T cells Tregs, and myeloid cells i.e. myeloid dendritic cells and myeloid-derived suppressor cells. In this reporting period, we have characterized the role of VISTA in controlling TLR-mediated activation of myeloid cells including DCs and macrophages, and myeloid-derived suppressor cells Aim 1 and identified potential signaling mechanisms whereby VISTA controls TAK1 activation and regulates the production of inflammatory cytokines. Second, we have established in vitro assay systems to distinguish T cell intrinsic versus extrinsic mechanisms whereby VISTA regulates TCR signaling and T cell activation. In addition, by following adoptively transferred T cells recognizing melanoma antigens, we have confirmed the synergistic activation of T cells in response to combinatorial therapy. These results form the foundation for defining the molecular mechanisms whereby the combinatorial therapy triggers potent anti-tumor T cell responses.