Project Grant F30CA294875

PROMOTING ACTIVATED NATURAL KILLER (NK) CELL ACCUMULATION IN PANCREATIC CANCER - PROJECT SUMMARY/ABSTRACT PANCREATIC DUCTAL ADENOCARCINOMA (PDAC) IS THE MOST COMMON FORM OF PANCREATIC CANCER, WITH A 5-YEAR SURVIVAL RATE OF ONLY 12%. IMMUNOTHERAPY, SUCH AS ANTI-PD1 ANTIBODY (A-PD1) TREATMENT, HAS BEEN LARGELY INEFFECTIVE IN PDAC. ALTHOUGH T CELLS AND NATURAL KILLER (NK) CELLS BOTH HAVE POTENT ANTI-TUMOR EFFECTS, MOST IMMUNOTHERAPY RESEARCH HAS FOCUSED ON MODULATING T-CELL ACTIVITY. THUS, THE FUNCTION OF NK CELLS IS HIGHLY UNDERSTUDIED IN PDAC. UTILIZING IMAGING MASS CYTOMETRY (IMC), A NOVEL MULTIPLEX IMAGING PLATFORM, OUR LABORATORY HAS MADE THE SURPRISING AND POTENTIALLY IMPORTANT OBSERVATION THAT ACTIVATED NK CELLS, BUT NOT T CELLS, PREFERENTIALLY CO-LOCALIZE WITH TUMOR EPITHELIAL CELLS IN THE PDAC TUMOR MICROENVIRONMENT (TME). THIS DISCOVERY WARRANTS INVESTIGATING STRATEGIES AND ANTI-TUMOR EFFECTS OF INCREASING CO-LOCALIZATION OF ACTIVATED NK AND TUMOR CELLS. HERE, WE DEMONSTRATE THAT PAN-INHIBITION OF DIPEPTIDYL PEPTIDASES (DPPS), ENZYMES KNOWN TO BE INVOLVED IN CANCER PROGRESSION AND BLOCKING IMMUNE ACTIVATION, USING THE PAN-DPP INHIBITOR BXCL701 (701) ENHANCES THE EFFICACY OF A-PD1 THERAPY IN SYNGENEIC, MURINE PDAC MODELS. THIS EFFECT IS ASSOCIATED WITH INCREASED NK CELL INFILTRATION, REDUCTION IN FIBROSIS, AND INCREASED EXPRESSION OF CXCL9, CXCL10, AND IL-18. NOTABLY, WE FOUND THAT INDIVIDUAL DPP INHIBITION DEMONSTRATES MINIMAL ANTI-TUMOR EFFECTS AS COMPARED TO PAN-DPP INHIBITION. FURTHERMORE, BY ANALYZING PUBLICLY AVAILABLE DATASETS AND IN VITRO ASSAYS, WE FOUND THAT THE NK CELL-ATTRACTANT CHEMOKINES CCL3 AND CXCL11 ARE RELATIVELY UNDEREXPRESSED IN PDAC. THIS SUGGESTS THAT CREATION OF SITE-SPECIFIC CHEMOKINE GRADIENTS USING CCL3/CXCL11 CAN SERVE TO INCREASE NK CELL ACCUMULATION. BASED ON THESE OBSERVATIONS, I HYPOTHESIZE THAT INCREASING CO-LOCALIZATION OF ACTIVATED NK CELLS WITH TUMOR CELLS IN PDAC WILL PROMOTE ANTI-TUMOR EFFECTS. TO TEST THIS HYPOTHESIS, I AIM TO DETERMINE THE IMPACT OF DPP INHIBITION ON THE SPATIAL AND FUNCTIONAL STATUS OF NK CELLS IN THE MURINE PDAC TME UTILIZING IMC (AIM 1A), ASSESS THE THERAPEUTIC IMPACT OF DEPLETING CXCL9, CXCL10, AND IL-18 ON ANTI-TUMOR EFFECTS MEDIATED BY 701+A-PD1 THERAPY IN VIVO (AIM 1B), AND MANIPULATE CCL3/CXCL11 EXPRESSION IN THE PDAC TME TO ENHANCE NK CELL MIGRATION IN VITRO (AIM 2A) AND ANTI-TUMOR RESPONSES IN VIVO (AIM 2B). SUCCESSFUL COMPLETION OF THESE AIMS WILL IDENTIFY FACTORS THAT REGULATE NK CELL INFILTRATION IN THE PDAC TME AND THE IMPACT OF NK CELL-TUMOR EPITHELIAL CELL CO-LOCALIZATION ON IMMUNE RESPONSES. THESE FINDINGS WILL FILL THE GAP IN KNOWLEDGE SURROUNDING INTRA-TUMORAL NK CELL MIGRATION, LOCALIZATION, AND FUNCTIONAL STATUS IN PDAC AND PROVIDE NEW APPROACHES FOR EXPLOITING NK CELLS TO ENHANCE ANTI-TUMOR IMMUNE ACTIVITY.