Pancreatic Cancer Immunotherapy

Pancreatic ductal adenocarcinoma (PDAC) is currently the 3rd leading cause of cancer-related death in the U.S. A Hallmark of PDAC is its fibrotic and immune suppressive tumor microenvironment that contributes to resistance to chemo- and immunotherapy. A major focus of our laboratory is to identify and target the multiples nodes of immune suppression in PDAC to activate ant-tumor immunity and potentiate currently ineffective immunotherapy regimens for this devastating disease. One approach we have taken has been to target mutant KRAS, the oncogenic driver found in >90% of PDAC, as a means to increase tumor immunogenicity. We discovered that a biological outcome of RAS pathway inhibition is cellular senescence, a stress-induced program that results in t­­he proliferative arrest of damaged cells and induction of a non-cell autonomous process called the senescence associated secretory phenotype (SASP) that can regulate tissue remodeling and immune responses. We are investigating how the SASP is regulated transcriptionally and extrinsically by the surrounding PDAC tumor microenvironment. We found a novel epigenetic regulatory mechanism through EZH2 that suppresses the pro-inflammatory SASP and whose targeting can lead to robust immune-mediated tumor clearance in pancreatic cancer. In addition to targeting the tumor directly, we have also uncovered therapeutic targets and are developing tools to reeducate immune suppressive stromal cells in the pancreas TME, including (a) fibroblast populations through remodeling their secretome and (b) myeloid populations through delivery of innate immune agonists and mRNA vaccines containing pro-inflammatory cytokines in collaboration with Dr. Prabhani Atukorale’s group. We believe that combinatorial targeting of tumor cell-autonomous and non-cell autonomous mechanisms of immune suppression can achieve immune-mediate tumor eradication of PDAC, a disease currently lacking in durable therapeutic regimens.