Our laboratory of Tumor Immunology and Immunotherapy is divided in two sections: Basic studies in immune tolerance and translational immunotherapeutic strategies in B-cell Lymphomas. Three major areas of research are being pursued in the area of basic studies of immune tolerance.
The first is to understand the cellular and molecular mechanism(s) involved in tolerance induction to tumor antigens including the role of Stat3/Stat1 signaling in determining activation versus tolerance in response to tumor antigens and that of histone deacetylase 11 (HDAC11) and histone deacetylase 6 (HDAC6) in regulation of IL-10 transcriptional activity and immune tolerance.
Second, we seek to design therapeutic strategies aimed to break this unresponsive state and enhance the efficacy of cancer immunotherapy. We are currently exploring whether strategies that block inhibitory pathways in APCs (i.e. Stat3 signaling) or strategies that induce inflammatory APCs (hystone deacetylase inhibitors) might overcome tumor induced antigen-specific T cell tolerance and enhance the efficacy of therapeutic cancer vaccination.
Thirdly, we seek to develop novel therapeutic cancer vaccines capable of breaking tolerance to tumor antigens. In the area of Translational Immunotherapeutic studies in B-cell lymphomas, our laboratory has found that generation of effective anti-lymphoma immunity requires: (1) Conversion of BM-derived APCs from a non-inflammatory (or tolerogenic) status into inflammatory APCs capable of triggering effective T-cell response and, (2) Augmentation of the antigen-presenting cell function of the malignant B-cell. Both requirements can be fulfilled by manipulation of molecular pathways that are involved in regulation of inflammatory responses in APCs as well as in the malignant B-cell. One of these pathways is represented by Stat3 signaling which has emerged as a negative regulator of inflammation. Pharmacological or genetic disruption of Stat3 in malignant mantle cell lymphoma (MCL) cells led to increased expression of co-stimulatory molecules, release of pro-inflammatory cytokines and augmentation of their antigen-presenting capabilities resulting in effective T-cell activation. In addition, we have also identified histone deacetylases as enticing targets to manipulate inflammatory responses in malignant B-cells. Currently, we are using both human MCL cell lines as well as primary cells from patients with MCL to test the hypothesis that inhibitors of Stat3 or histone deacetylases by abrogating anti-inflammatory mechanisms and/or promoting inflammatory pathways in malignant B-cells will unleash effective anti-MCL immunity.