PROJECT SUMMARY/ABSTRACT
Pancreatic ductal adenocarcinoma (PDAC) is a devastating malignancy characterized by a fibrotic and
immunosuppressive tumor microenvironment. Innovative approaches to overcome the lack of an effective
immune response in PDAC are desperately needed. Although the concept of therapeutic infection, using
bacteria as immunotherapy, has been around for over a century, recent advances in our understanding of
bacterial interaction with immune cells and molecular pathways with relevance in cancer suggest new
opportunities to harness natural bacterial immunomodulatory properties in PDAC. We have developed
preliminary data demonstrating that injection of Group A Streptococcus (GAS) activates anti-tumor immunity
resulting in profound tumor regression in murine pancreatic cancer. We have identified an extracellular
protein, Scl1, on GAS, which selectively binds oncofetal fibronectin (cFn) in the pancreatic tumor
microenvironment, suggesting the potential for bacterial localization to pancreatic tumors. Importantly, cFn is
expressed in pancreatic tumors, but not healthy tissues, therefore Scl1/cFN interaction may be harnessed as a
mechanism to limit off-target effects of PDAC treatment following direct injection into tumors. Additionally, we
have discovered that Scl1 on GAS blocks cancer promoting neutrophil extracellular traps (NETs). Since NETs
are responsible for promotion of tumor growth, metastatic disease and immunosuppression in PDAC, this has
tremendous implications for utilizing GAS-Scl1 to alter cancer pathogenesis and anti-tumor immunity. Tumor
growth and survival after intra-tumoral injection of 3 unique strains of GAS will be assessed in murine
orthotopic, metastatic and transgenic PDAC. The formation and structure of GAS microcolonies within tumors
will be imaged by two-photon microscopy. Circulating and intra-tumoral NETs after GAS injection will be
measured and a robust immune profile generated to identify immunomodulatory effects. The proposed grant
will decipher novel mechanisms driving the capability of GAS-Scl1 to stimulate anti-tumor immunity and
elucidate the therapeutic potential of non-infectious strategies harnessing GAS-Scl1 in a future treatment for
PDAC .