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Regulation of the innate immune response in the tumor microenvironment of lung adenocarcinoma

Award Number: K01CA255406
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Regulation of the innate immune response in the tumor microenvironment of lung adenocarcinoma - Lung cancer is responsible for more deaths in the United States than any other form of cancer. Unfortunately, many lung cancer patients do not respond to treatments that effectively mobilize cytotoxic T cells against tumors in other cancers (e.g. anti-PD-1/PD-L1 and anti-CTLA4). This lack of response in lung cancer is primarily due to an inability to initiate a robust antitumor immune response. Lung cancer cells secrete the damage-associated molecular pattern protein, High Mobility Group Box 1 (HMGB1) which has a dual function in immunity. Although it can facilitate immune cell infiltration into tumors; its predominant function is to drive the secretion of negative immune regulators including TGF-b and IL-10 and increase expression of programmed death receptor ligand 1 (PD-L1). My preliminary data suggest that monounsaturated fatty acids (MUFA) are required to prevent HMGB1 secretion from lung cancer cells. Therefore, I hypothesize that lung cancer patients with lower concentrations of tumor-associated MUFA will have higher expression of HMGB1 resulting in an immunosuppressive tumor microenvironment (TME). To test this hypothesis, I propose two Specific Aims: 1) Determine the association between MUFA, extracellular HMGB1, and lung cancer in patients; 2) Evaluate the effects of MUFA on secretion of HMGB1 and the activation of cancer-associated fibroblasts in ex vivo tumor models. I will use lipidomic and immunological assays to determine the association between MUFA and secreted HMGB1 in lung cancer patients. Using patient tissue explants, I will measure the effects of pharmacologic inhibition of MUFA on secretion of HMGB1. To study the effects of genetic and pharmacologic inhibition of MUFA on the TME, I will construct vascularized 3-dimensional bioprinted lung tumors constructed using lung cancer cells and lung fibroblasts. This will allow characterization of immune modulating cytokines secreted by cancer-associated fibroblasts, a dominant cell type within lung tumors. The long-term goal of this research is to provide insight into the mechanisms by which tumors orchestrate immune suppression, and enable the development of new strategies to overcome this immunological barrier. This K01 proposal is designed to build upon my training background and track record in basic molecular and cancer biology, and expand my skills as a translational researcher. My scientific advisory committee is composed of accomplished scientists and clinicians with expertise in oncology, lung disease, lipid biochemistry, fibroblast biology and molecular biology. The program outlined in this K01 proposal will propel me into an independent scientific career through rigorous career development activities tailored to my specific research goals.


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 = $152,499 )
2025	2025	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	000	6	8/12/2025	NON-COMPETING CONTINUATION	$152,499
														Subtotal = $152,499

Issue Date FY: 2024 ( Subtotal = $228,099 )
2024	2024	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	000	5	7/16/2024	NON-COMPETING CONTINUATION	$228,099
														Subtotal = $228,099

Issue Date FY: 2023 ( Subtotal = $174,204 )
2023	2023	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	001	4	7/7/2023	NON-COMPETING CONTINUATION	$152,499
2023	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	000	2	1/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$21,705
														Subtotal = $174,204

Issue Date FY: 2022 ( Subtotal = $152,500 )
2022	2022	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	004	3	8/19/2022	NON-COMPETING CONTINUATION	$152,499
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Research Manpower	002	1	6/30/2022	NEW	-$1
2022	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	003	2	6/30/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$1
2022	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Research Manpower	000	1	5/16/2022	NEW	-$130,793
2022	2021	CORNELL UNIVERSITY	341 PINE TREE RD	ITHACA	NY	14850	TOMPKINS	USA	Cancer Research Manpower	001	2	5/16/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$130,794
														Subtotal = $152,500

Issue Date FY: 2021 ( Subtotal = $130,794 )
2021	2021	REGENTS OF THE UNIVERSITY OF MINNESOTA	200 OAK ST SE # 224	MINNEAPOLIS	MN	55455	HENNEPIN	USA	Cancer Research Manpower	000	1	7/26/2021	NEW	$130,794
														Subtotal = $130,794

Grand Total All Awards = $838,096

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Regulation of the innate immune response in the tumor microenvironment of lung adenocarcinoma

Award Number: K01CA255406

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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