Mechanisms of Dectin-2 agonist therapy for treatment of pancreatic ductal adenocarcinoma (PDAC) - PROJECT SUMMARY
Pancreatic ductal adenocarcinoma (PDAC) accounts for almost 3% of all cancer and 7% of cancer deaths in the
United States and has a poor five-year survival rate (~9%). Currently, the main treatment strategy is surgical
resection followed by chemotherapy, but this strategy is not successful in the majority of patients with PDAC.
Checkpoint blocking immunotherapies are drugs that activate the host immune system to target cancer cells and
have emerged as an effective therapeutic strategy for the treatment of some cancers. However, PDAC has been
largely resistant to these and other immunotherapeutic strategies. The tumor microenvironment in PDAC
contains many immunosuppressive tumor associated macrophages (TAMs) that may contribute to the
ineffectiveness of current immunotherapeutic strategies. Our group recently discovered that the
immunosuppressive macrophages in the PDAC microenvironment express high levels of a surface receptor,
Dectin-2, which is not highly expressed elsewhere in the body. Dectin-2 normally recognizes mannose-rich
microbial components as part of the host defense, however, Dectin-2 has not been explored in cancer. Our group
recently found that activation of Dectin-2 through a natural ligand, mannan, induces immunoreactivity and tumor
regression in a mouse model of PDAC. Our hypothesis is that in response to Dectin-2 activation, TAMs undergo
reprogramming and the tumor microenvironment transitions from an immunosuppressive to an
immunostimulatory environment, allowing for the infiltration of anti-tumor effector T cells and tumor regression.
The goals of this fellowship are, therefore, to elucidate the mechanisms by which Dectin-2 activation leads to
PDAC tumor regression in an effort to advance this therapeutic strategy toward clinical use. To this end, our
proposal sets out to accomplish two goals. 1) Investigate the local and systemic effects of Dectin-2
stimulation on tumor burden and the immune response in PDAC mice; 2) Evaluate the role of tumor
associated macrophages (TAMs), T effector cells, and GM-CSF signaling in the response to Dectin-2
agonist in PDAC. RNA-sequencing and CyTOF of mouse models of PDAC with and without Dectin-2 agonist
treatment will be utilized to investigate changes that occur in the macrophages, TME, and systemic immune
system in response to treatment. Additionally, genetic knockout mouse models of the proposed molecular
mediators will be utilized to confirm the mechanism of Dectin-2 agonist therapy. Finally, human PDAC tissues
will be evaluated for Dectin-2 expression and correlated to tumor genotype. The work completed during this
fellowship will lead to a novel immunotherapeutic strategy to overcome the immunosuppressive tumor
microenvironment for the treatment of PDAC. Through the study of cellular and molecular mediators of Dectin-2
agonist therapy there is also potential to identify additional targets relevant for evoking an anti-tumor immune
response. Ultimately, the work outlined in this proposal provides the foundation necessary for creating effective
therapy for PDAC.
