The Datta Lab is pursuing the following projects:

1. The role of MDSC-derived tumor necrosis factor (TNF) in regulating stromal inflammation and T-cell dysfunction: Our lab recently reported the previously unrecognized role of MDSC-derived TNF as a central regulator of inflammatory fibroblast polarization and CD8+ T-cell dysfunction in PDAC (Cancer Discov 2023: https://bit.ly/3lJoIZy). We also showed that these effects are mediated by preferential signaling through transmembrane TNF (tmTNF) and TNFR2 in the tumor microenvironment. We are now actively exploring the signaling crosstalk and spatial interactions between MDSC-derived tmTNF and CAF-TNFR2 as well as T-cell-TNFR2 and how these may be critical determinants of chemoimmunotherapy resistance in PDAC. We are very interested in understand mechanisms that are involved in regulating TNF transcription as well as membrane sequestration in MDSCs. We are also developing highly selective pharmacotherapy targeting TNFR2 signaling to reprogram MDSC-CAF spatial habitats and an inflammatory CAF-dominant stroma to augment chemoimmunotherapy sensitivity in PDAC in vivo. This work has been/is currently supported by the Elsa Pardee Foundation, Pancreatic Cancer Action Network, Association for Academic Surgery, and the American College of Surgeons.
   
   
2. The role of inflammasome activation induced IL-1beta from MDSCs in promoting stromal and immune dysfunction in PDAC: With the support from Department of Defense Idea Development, we will determine if conditional silencing of MDSC-derived inflammasome activation disrupts evolution of inflammatory CAF phenotypes and improves chemosensitivity in preclinical models. We will also examine if spatial proximity of inflammasome-competent MDSCs with pro-inflammatory CAFs in human tumors correlates with resistance to chemotherapy in localized PDAC.
   
   
3. Immunonanoengineering strategies to disrupt tolerogenic signaling from MDSCs: We are actively developing neutrophil-homing immunonanoparticles to deploy diverse payloads directly to MDSCs. These strategies, which we are developing using FDA-approved polymer engineering backbones for ease of clinical translation, will target pathways such as arginase, inflammasome activation, and membrane sequestration of TNF, for example.
   
   
4. Phenotypic and functional heterogeneity of MDSCs: Using single-cell RNA sequencing and spatial methodologies, we are exploring the diversity and functional plasticity of neutrophilic MDSCs in murine and human models of pancreatic cancer. Using lineage trajectory inference, we are interested in understanding the developmental evolution of these MDSC subsets, the transcriptional networks underlying these fate transitions, and their correlation with oncologic outcomes in PDAC patients.
   
   
5. Using lab-on-a-chip to reconstruct dynamics of cellular crosstalk in the pancreatic tumor microenvironment: In a collaboration funded by an intramural grant by Sylvester, we are working with Dr. Ashutosh Agarwal in the Bioengineering Dept to engineer a biomimetic pancreatic microenvironment on a chip to investigate dynamic MDSC-CAF interactions that dictate chemoresistant signaling, and utilize this PDAC-mimetic chip to accelerate screening of therapeutics targeting key pathways in MDSCs to disrupt inflammatory CAF polarization.