Research:
Identifying treatment strategies to increase immune cell accumulation in pancreatic cancer in order to improve patient responses to immunotherapy. Specifically, utilizing high-throughput single-cell proteomic analysis technologies to identify immune cell populations that promote anti-tumor effects in pancreatic cancer.

How Will Your Research Benefit Society?

Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer. PDAC has a 5 year survival rate of 12% and current treatments are limited to toxic chemotherapies. Immunotherapy utilizes the body’s own immune system to fight cancer, but has had limited success in pancreatic cancer due to the immunosuppressive nature of the PDAC tumor microenvironment (TME). Significantly, the PDAC TME restricts accumulation of anti-cancer immune cells at the site of tumor cells by promoting fibrosis. Previously, we have found that dipeptidyl peptidases (DPPs), a family of serine peptidases involved in fibrosis and cancer, are overexpressed in PDAC. Four kinds of DPPs and Fibroblast Activation Protein (FAP) possess enzymatic activity, which limit immune activating cytokines and promote fibrosis. Interestingly, BXCL701 (701), a pan-inhibitor of these DPPs and FAP, enhances the anti-tumor effects of anti-PD1 antibody (α-PD1) immunotherapy in syngeneic, murine PDAC models. Using imaging mass cytometry, I have found that 701+α-PD1 induces a dramatic reduction in intra-tumoral collagen and αSMA+ fibroblasts. Critically, this is associated with increased T cell infiltration. However, despite these findings, the full impact of 701+α-PD1 on activating immune cells responsible for anti-tumor effects in the PDAC TME is unclear. Therefore, to fully interrogate the effects of this therapy, I propose to use a multiplex, single cell proteomic technology called cytometry by time-of-flight (CyTOF) to characterize and define alterations in up to 40 different immune cell sub-populations induced by 701+α-PD1 treatment responsible for anti-tumor effects. These results will provide insights into the impact of DPP inhibition on activating different immune cell subsets and potentially identify unique populations responsible for anti-tumor effects in PDAC. Most excitingly, results will be rapidly translatable, given that my advisor, Dr. Louis M. Weiner, is directing a phase II clinical trial testing 701+α-PD1 in patients with metastatic PDAC.

How will an ARCS Award Benefit Your Research?

Although spatial proteomic imaging technologies are increasing in popularity, reagent costs are still a barrier. This second year as an ARCS scholar will allow me to further overcome these barriers to address my hypothesis and progress my thesis project.

Career objectives:

My goal is to become a leading physician-scientist in the field of cancer immunology, working to develop new therapies for pancreatic cancer. Simultaneously, I hope to serve as a leader for the next generation of scientists, advocating for science education and research.