The long term of our studies is to understand the immunobiology of the immunosuppressive/proangiogenic leukocytes that phenotypically resemble dendritic cells and distinctively accumulate in human and mouse ovarian cancer, termed by us Vascular Leukocytes (VLCs). This proposal focuses on comprehending the molecular factors that ultimately drive the tolerogenic activity and selective accumulation of VLCs (and regulatory DCs in general) at tumor locations. Key findings for the ongoing grant have been: The overexpression of special AT-rich sequence binding protein 1 (Satb1), a master programmer controlling genome-wide transcriptional programs17, in the nuclei of tumor VLCs, in both mice and humans;the co-localization of ?-catenin with Satb1;and the abrogation of the immunosuppressive phenotype of VLCs by in vivo Satb1 silencing. Based on these and other findings, our central hypothesis is that Satb1 is the master programmer of the immunosuppressive activity and preferential accumulation of regulatory DCs/VLCs in ovarian cancer. Because virtually nothing is known about the role of Satb1 in myeloid leukocyte subsets, we have generated for these studies a novel conditional knockout mouse model, developed a better genetic model of ovarian cancer, and optimized silencing tools for in vivo use. With these unique resources in hand, we propose to focus the application on the following three specific aims:
In Specific Aim 1, we will define how Satb1 is the primary driver of the immunosuppressive properties of ovarian cancer-associated VLCs.
In Specific Aim 2, we will define the role of Satb1 in the accumulation of regulatory DCs/VLCs within ovarian cancer.
In Specific Aim 3, we will establish the molecular factors modulating the overexpression of Satb1 in regulatory DCs/VLCs in ovarian cancer. Our work will exert a profound effect in the field by defining Satb1 - a global organizer of genome-wide transcriptional programs - as the master regulator ultimately driving the immunosuppressive activity and preferential accumulation of VLCs in ovarian cancer, which will be applicable to regulatory DCs in other lethal tumors and has obvious implications for development of improved immunotherapies.
Epithelial ovarian cancer kills ~15,000 Americans per year. Over the last 30 years, despite extensive research into the cell cycle and tumor cell mutations, the very poor 5- year survival rates are unchanged. Current immunotherapies rarely induce the regression of lethal epithelial cancers, due in part to an incomplete understanding of the mechanisms of tumor-induced immune evasion. The accomplishment of the proposed aims will define Satb1 as the master regulator driving the immunosuppressive phenotype and pathological mobilization of regulatory myeloid leukocytes in ovarian cancer. This understanding will provide a mechanistic rationale for new advances towards chemoprevention, early detection and effective treatment of this devastating disease, which may be applicable to other lethal epithelial tumors.
|Rabinovich, Gabriel A; Conejo-GarcÃa, JosÃ© R (2016) Shaping the Immune Landscape in Cancer by Galectin-Driven Regulatory Pathways. J Mol Biol 428:3266-81|
|Conejo-Garcia, Jose R; Rutkowski, Melanie R; Cubillos-Ruiz, Juan R (2016) State-of-the-art of regulatory dendritic cells in cancer. Pharmacol Ther 164:97-104|
|Allegrezza, Michael J; Rutkowski, Melanie R; Stephen, Tom L et al. (2016) Trametinib Drives T-cell-Dependent Control of KRAS-Mutated Tumors by Inhibiting Pathological Myelopoiesis. Cancer Res 76:6253-6265|
|Sheen, M R; Marotti, J D; Allegrezza, M J et al. (2016) Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer. Oncogenesis 5:e267|
|Svoronos, Nikolaos; Perales-Puchalt, Alfredo; Allegrezza, Michael J et al. (2016) Tumor Cell-Independent Estrogen Signaling Drives Disease Progression through Mobilization of Myeloid-Derived Supressor Cells. Cancer Discov :|
|Tesone, Amelia J; Rutkowski, Melanie R; Brencicova, Eva et al. (2016) Satb1 Overexpression Drives Tumor-Promoting Activities in Cancer-Associated Dendritic Cells. Cell Rep 14:1774-86|
|Allegrezza, Michael J; Rutkowski, Melanie R; Stephen, Tom L et al. (2016) IL15 Agonists Overcome the Immunosuppressive Effects of MEK Inhibitors. Cancer Res 76:2561-72|
|Rutkowski, Melanie R; Stephen, Tom L; Svoronos, Nikolaos et al. (2015) Microbially driven TLR5-dependent signaling governs distal malignant progression through tumor-promoting inflammation. Cancer Cell 27:27-40|
|Rutkowski, Melanie R; Conejo-Garcia, Jose R (2015) Size does not matter: commensal microorganisms forge tumor-promoting inflammation and anti-tumor immunity. Oncoscience 2:239-46|
|Cubillos-Ruiz, Juan R; Silberman, Pedro C; Rutkowski, Melanie R et al. (2015) ER Stress Sensor XBP1 Controls Anti-tumor Immunity by Disrupting Dendritic Cell Homeostasis. Cell 161:1527-38|
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