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Regulation of Cross-Tolerance to Tumor Antigens

Eduardo M. Sotomayor

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National Institutes of Health (NIH)
Tumor-induced T-cell tolerance imposes a remarkable barrier to cancer immunotherapy. Bone marrow (BM) derived APCs play a central role in the induction of this state of unresponsiveness to tumor antigens. During the prior funding period of this grant, we have identified several signaling pathways that, by regulating the inflammatory status of the APC are critical in the decision leading to T-cell activation versus T-cell tolerance. More recently, we have focused our attention to mechanistically understand the regulation of inflammatory/anti-inflammatory genes in its natural setting, the chromatin substrate. In particular, we have studied the consequences of chromatin modification mediated by histone deacetylases upon the expression of genes involved in the inflammatory response. Our studies have unveiled for the first time that the histone deacetylase 11 (HDAC11) negatively regulates the expression of the anti-inflammatory cytokine IL-10 in murine and human APCs. Such an effect not only determines the inflammatory status of these cells but also influence priming versus tolerance of antigen-specific CD4+ T cells. In addition, we have found that histone deacetylase 6 (HDAC6) induce the opposite effect, i.e. enhanced IL-10 gene expression. These observations along with our recent finding that HDAC11 and HDAC6 interact with each other provide the framework to mechanistically address their role in regulating inflammatory responses in APCs and T-cells. The hypothesis to be tested is that dynamic changes at the chromatin level induced by HDAC6 and/or HDAC11 might influence the intrinsic plasticity of the APC to determine T-cell activation versus T-cell tolerance. The combination of experimental tools and animals models of T-cell tolerance we have developed during the past several years, together with the availability of mice with genetic disruption of HDAC11 or HDAC6 would allow us to determine whether these HDACs regulate inflammatory responses in murine and human APCs (Aim 1) and to assess their role in influencing CD4+ T-cell priming versus tolerance to tumor antigens in vivo (Aim 2). In addition, we propose studies to gain insights into the molecular mechanism(s) by which HDAC6 and HDAC11 regulate inflammation and the development of immunity versus tolerance (Aim 3). We believe that this comprehensive, mechanistically-oriented and translational project would unveil novel targets to overcome the barrier that tolerance to tumor antigens has imposed to the field of cancer immunotherapy.

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