ABSTRACT
Pancreatic Ductal Adenocarcinoma (PDAC) is a highly lethal disease and is expected to become the second
leading cause of cancer-associated-death in the US by the year 2025. Targeted therapeutics have failed to
provide a significant survival advantage over the standard of care. With an intensified focus on immunotherapy,
immune checkpoint blockade (ICB) therapies alone have been insufficient for PDAC, which often displays a non-
immunogenic “cold” tumor phenotype that lacks cytotoxic T lymphocyte (CTL) infiltration, thus incapable of
invoking an immune response. To this point, we have learned that multiple biological and molecular aspects of
PDAC contribute to ICB efficacy; including antigenicity, immunogenicity, and the tumor microenvironment.
Finding targeted therapeutics to increase these aspects of immunity and increase intratumoral T cell infiltration
are essential for improving immunotherapeutic applications for PDAC.
Obesity is a prominent risk factor for development of PDAC as well as more advanced disease. Obesity
is well evidenced to drive local adipose inflammation, but also contributes to systemic inflammation. Our recent
findings indicate adipose derived cytokines directly modulate the transcriptional profile of PDAC cells.
Specifically, we found that stimulation of PDAC cells with adipose conditioned media promoted anti-immunogenic
chemokine secretion of tumor-derived CXCL5, which is a ligand of the CXCR1/2 receptors that typically regulates
myeloid recruitment and/or activation. While clinical trials targeting the CXCR1/2 receptors with pharmacologic
inhibitors have entered clinical trials, their efficacy in PDAC is questionable due to broad receptor expression
and conflicting results. In comparison, our studies have demonstrated that depleting tumor derived CXCL5, one
of many CXCR1/2 ligands, is sufficient to promote intratumoral CTL infiltration and prime the tumor for checkpoint
inhibition in the setting of obesity.
In general, targeting pancreatic cancers with cell-specific biomarkers has presented a challenge to
researchers, as some biomarkers of PDAC are highly expressed in non-cancerous tissues and limiting drug
delivery to non-cancerous tissue is essential for minimizing side effects. The Plectin protein represents an ideal
biomarker for targeted therapeutic delivery. In healthy cells, Plectin maintains a cytoplasmic localization where
it is hidden from targeted therapeutics. Alternatively, Plectin is exclusively externalized in pancreatic cancer cells
where it provides an optimal target for drug delivery. Proof of principle studies have validated PDAC specific
binding of Plectin targeted AAV viral particles. We plan to package shRNA for CXCL5 into the Plectin-AAV
particles to recapitulate our CRISPR studies and induce susceptibility to ICB therapy in an obese setting.
