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Understanding Pancreatic Cancer Immune Microenvironment and Treatment Response through Integrating in vivo Imaging with Immunophenotyping

Award Number: R01CA278941
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Understanding Pancreatic Cancer Immune Microenvironment and Treatment Response through Integrating in vivo Imaging with Immunophenotyping - Project Summary Although cancer immunotherapy has been proclaimed a breakthrough in many types of cancer, pancreatic ductal adenocarcinoma (PDAC) responds poorly to immune checkpoint blockade (ICB) therapy. PDAC is classified as immunologically “cold” tumor with pronounced presence of immunosuppressive myeloid cells. Therefore, developing novel approaches to reprogram the PDAC tumor immune microenvironment (TiME) and promoting immunotherapeutic efficacy are drastically needed. A key knowledge gap in understanding the PDAC TiME is a lack of tools to visualize and monitor these immunosuppressive myeloid cells during tumor progression and treatment. Molecular imaging approaches provide such an opportunity through a specific cell-tracking strategy or targeting of surface molecules expressed on immune cells. In the preliminary studies, we demonstrated that yeast-derived whole b-glucan particles (WGP) predominately traffic to the pancreas and incite massive infiltration of myeloid cells with trained immunity phenotype, leading to a reduction in PDAC tumor progression and prolonged survival. Trained immunity is defined as innate immune responses that can adapt and develop a memory-like phenotype of previous infection or vaccination. Despite these successes, mice treated with WGP eventually died even in combination with anti- PD-L1 therapy. The overarching goal of this proposal is to develop an integrated in vivo imaging with immunophenotyping approach to understand PDAC immune evasion mechanisms and develop more efficacious therapy for PDAC. Three Aims are proposed. Aim 1 will determine if induction of trained immunity reprograms pancreas myeloid cells thus reshaping their function in the PDAC TiME. We will utilize a radiolabeled WGP and an anti-CD11b probe to track WGP trafficking and influx of myeloid cells in the pancreas. We will also test the hypothesis that the abundance of pancreas tissue resident macrophages (TRMs), as measured by the lymphatic vessel endothelial hyaluronan receptor (LYVE-1) probe, is a predictive marker for PDAC immune evasion and progression. Aim 2 will determine whether combining trained immunity with anti-CD47 and/or anti-EGFR mAb therapy promotes myeloid cell phagocytic/tumoricidal activity to maximize innate antitumor immunity. Targeted in vivo imaging will be used to monitor phagocytosis and EGFR levels within the PDAC TiME. Aim 3 will determine the ability of induction of trained immunity to recruit and stimulate adaptive T cells in the pancreas. We will also determine whether combining induction of trained immunity with anti-CD47 mAb therapy will further potentiate anti-PD-L1 therapeutic efficacy in PADC. Immuno-imaging will be used to track CD8+ T cell infiltration, function, and PD-L1 expression within the PDAC TiME. The successful completion of this proposal will likely provide a novel insight into understanding the mechanisms of PDAC immune evasion and treatment response and resistance.


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: 2025 ( Subtotal = $584,526 )
2025	2025	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Detection and Diagnosis Research	000	2	2/17/2025	NON-COMPETING CONTINUATION	$584,526
														Subtotal = $584,526

Issue Date FY: 2024 ( Subtotal = $649,473 )
2024	2024	UNIVERSITY OF LOUISVILLE	2301 S 3RD ST	LOUISVILLE	KY	40208	JEFFERSON	USA	Cancer Detection and Diagnosis Research	000	1	3/8/2024	NEW	$649,473
														Subtotal = $649,473

Grand Total All Awards = $1,233,999

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Understanding Pancreatic Cancer Immune Microenvironment and Treatment Response through Integrating in vivo Imaging with Immunophenotyping

Award Number: R01CA278941

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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