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.
The immune system is equipped with cells (T-lymphocytes) that if properly activated can identify and destroy cancer cells. However, malignant cells have developed mechanisms to block the effect of these immune cells. Among those mechanism(s), the ability of tumor cells to induce tolerance or paralysis of T-lymphocytes is considered a major barrier to effectively harness the immune system against cancer. During the past ten years, our laboratory has been at the forefront of identifying the mechanism(s) by which tumors induce this state of unresponsiveness of immune cells. For instance, we found that tumor cells require the presence of bone marrow-derived antigen-presenting cells (APCs) for the induction of T-cell tolerance. Furthermore, we have identified intracellular signaling pathways in the APC that are central in the decision leading to T-cell tolerance versus T-cell activation in response to tumor antigens. More recently, we have identified two molecules with enzymatic activity named histone deacetylase 11 (HDAC11) and histone deacetylase 6 (HDAC6) as playing an important role in influencing the function of APCs and T-lymphocytes. The goal of this application is therefore to better understand the role of HDAC11 and HDAC6 in tumor-induced T-cell tolerance and design novel therapies to manipulate these molecules and overcome tolerance to tumor antigens.
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|Cheng, Fengdong; Lienlaf, Maritza; Wang, Hong-Wei et al. (2014) A novel role for histone deacetylase 6 in the regulation of the tolerogenic STAT3/IL-10 pathway in APCs. J Immunol 193:2850-62|
|Cheng, Fengdong; Lienlaf, Maritza; Perez-Villarroel, Patricio et al. (2014) Divergent roles of histone deacetylase 6 (HDAC6) and histone deacetylase 11 (HDAC11) on the transcriptional regulation of IL10 in antigen presenting cells. Mol Immunol 60:44-53|
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|Brayer, Jason; Cheng, Fengdong; Wang, Hongwei et al. (2010) Enhanced CD8 T cell cross-presentation by macrophages with targeted disruption of STAT3. Immunol Lett 131:126-30|
|Vicente-Suarez, Ildelfonso; Brayer, Jason; Villagra, Alejandro et al. (2009) TLR5 ligation by flagellin converts tolerogenic dendritic cells into activating antigen-presenting cells that preferentially induce T-helper 1 responses. Immunol Lett 125:114-8|
|Horna, Pedro; Sotomayor, Eduardo M (2007) Cellular and molecular mechanisms of tumor-induced T-cell tolerance. Curr Cancer Drug Targets 7:41-53|
|Vicente-Suarez, Ildefonso; Takahashi, Yoshinori; Cheng, Fengdong et al. (2007) Identification of a novel negative role of flagellin in regulating IL-10 production. Eur J Immunol 37:3164-75|
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