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Pancreatic Stellate Cell (PSC) Engagement of Natural Killer (NK) cells in the Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment

Award Number: F31CA261125
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY/ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the most common form of pancreatic cancer, with a 5-year survival rate of less than 10%. One of the hallmarks of PDAC is immune suppression, which is mediated in part by a heterogenous cancer-associated fibroblast (CAF) population, also termed pancreatic stellate cells (PSCs). PSCs can exist as both tumor-promoting and tumor-restrictive subpopulations. Our laboratory recently showed that human natural killer (NK) cells interact with and lyse activated PSCs via a NKG2D-MICA/B NK cell receptor- ligand interaction. NK cells are cytotoxic components of the innate immune system; their functions are highly understudied in PDAC. Our laboratory also had made the novel and potentially important observations that activated, cytotoxic, NK cells are relatively abundant in the PDAC tumor microenvironment (TME), and that high expression of NK cell markers correlates with better PDAC patient survival. Based on these observations, I hypothesize that one important role of PSCs is to divert NK cells from malignant epithelial PDAC cells in the tumor microenvironment (TME), protecting tumors from immune attack. Therefore, this project’s first aim is to explore the interactions between fibroblast activation protein (FAP)+ PSCs with NK cells in PDAC. NK cell receptor-ligand interactions that regulate NK cell-mediated lysis of FAP+ PSCs will be further studied in vitro. The spatial relationships between NK cells and FAP+ PSCs will also be defined using a human PDAC tumor microarray by Imaging Mass Cytometry. The second aim is to examine the impact of NK cells and FAP+ PSCs on tumor growth. In a murine PDAC model, FAP+ PSCs will be depleted using a FAP-specific catalytic immunotoxin to assess the impact of FAP+ PSC depletion on PDAC and NK cell invasion, phenotype, and function. NK cells will also be selectively depleted in a murine PDAC model in order to determine their impact on tumor growth, FAP+ PSC phenotype and function in the PDAC TME. This work will employ single-cell RNA sequencing analysis to assess transcriptional changes in the PDAC TME as a function of these depletion studies. Combinations of NK cell enhancement/activation with FAP+ PSC depletion will define the potential translational relevance for future therapy strategies. Successful completion of these aims will elucidate the relevance of NK cell-PSC interactions in PDAC and will lay the groundwork for exploiting the innate immune system to increase the efficacy of the anti-tumor immune response.


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: 2024 ( Subtotal = $0 )
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	3	8/9/2024	NON-COMPETING CONTINUATION	-$36,274
2024	2024	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	3	7/11/2024	NON-COMPETING CONTINUATION	$36,274
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $34,994 )
2023	2023	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	2	9/6/2023	NON-COMPETING CONTINUATION	$34,994
														Subtotal = $34,994

Issue Date FY: 2022 ( Subtotal = $34,052 )
2022	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	001	1	9/1/2022	NEW	$0
2022	2022	GEORGETOWN UNIVERSITY	MAIN CAMPUS	WASHINGTON	DC	20057	DISTRICT OF COLUMBIA	USA	Cancer Research Manpower	000	1	9/1/2022	NEW	$34,052
														Subtotal = $34,052

Grand Total All Awards = $69,046

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Pancreatic Stellate Cell (PSC) Engagement of Natural Killer (NK) cells in the Pancreatic Ductal Adenocarcinoma (PDAC) Tumor Microenvironment

Award Number: F31CA261125

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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