2022 Grantee: Jashodeep Datta, MD
University of Miami
Research Project: A Novel Mechanism of MDSC-mediated Stromal and T-cell Dysregulation in PDAC
Award: 2022 Pancreatic Cancer Action Network Career Development Award, funded by an anonymous donor
Award Period: July 1, 2022 – June 30, 2024
Dr. Datta is an Assistant Professor of Surgery and a hepatobiliary and pancreatic surgical oncologist at the University of Miami Miller School of Medicine and Sylvester Comprehensive Cancer Center in Miami, Fla. He is also the Associate Director of Translational Research at the Sylvester Pancreatic Cancer Research Institute. As a surgeon-scientist, his laboratory in pancreatic cancer immunology focuses on understanding how tumor cell-intrinsic transcriptional programs orchestrate immune suppression in the pancreatic tumor microenvironment, specifically deciphering and targeting the dominant tolerogenic signaling mechanisms in myeloid-derived suppressor cells (MDSC) that govern T-cell dysfunction and stromal inflammation. He is also developing novel nanoengineering strategies for compartment-specific targeting of such tolerogenic functions in MDSCs. His clinical and translational research interests are in optimizing the physiologic and biologic selection of patients for neoadjuvant therapies in pancreatic cancer and leveraging the neoadjuvant platform to discover novel predictive biomarkers of therapeutic response and resistance.
For this project, Dr. Datta describes three key culprits for pancreatic cancer’s resistance to chemotherapy and immunotherapy treatments. First, early and frequent infiltration of tumors by immunosuppressive immune cells – specifically neutrophilic MDSCs – that repel T-cell-mediated immune responses against the tumor. Second, another cell type, known as cancer-associated fibroblasts, which imbibe multifaceted cues from the tumor microenvironment to promote stromal inflammation by transmitting signals to further beckon MDSCs to the tumor milieu. And third, T-cells, immune cells that would typically recognize and attack the cancer cells as foreign, which are rendered impotent largely from suppressive signaling originating from MDSCs.
Dr. Datta and his team have identified that MDSCs are the dominant cellular source of tumor necrosis factor (TNF) in pancreatic cancers, and that TNF is a previously unrecognized regulator of stromal inflammation and T-cell dysfunction in pancreatic cancer. In a mouse model of pancreatic cancer, disruption of MDSC-derived TNF inhibited immunosuppressive inflammatory signaling and caused cancer-fighting T-cells to become activated and enter the tumor microenvironment.
Building on these observations, the goal of this proposal is to better understand the mechanism of MDSC-derived TNF in mediating stromal and T-cell dysregulation in the pancreatic tumor microenvironment using novel mouse modeling techniques and single-cell spatial imaging technologies in human pancreatic tumors. Dr. Datta and his team will also investigate if pharmacologic disruption of this MDSC-mediated stromal-immune dysregulation can improve pancreatic tumors’ sensitivity to chemotherapy in mouse models that phenocopy human disease. Ultimately, successful completion of this proposal will support development of an MDSC-directed immunotherapeutic strategy to overcome treatment resistance in pancreatic cancer patients.