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Mechanisms of Dectin-2 agonist therapy for treatment of pancreatic ductal adenocarcinoma (PDAC)

Award Number: F32CA254250
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 06/15/2021

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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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	1	2/3/2021	NEW	$1,056
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	1	4/28/2021	NEW	-$65,610
2021	2021	LELAND STANFORD JUNIOR UNIVERSITY, THE	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	12/15/2020	NEW	$64,554
														Subtotal = $0

Grand Total All Awards = $0

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Mechanisms of Dectin-2 agonist therapy for treatment of pancreatic ductal adenocarcinoma (PDAC)

Award Number: F32CA254250

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 06/15/2021

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