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Metabolic Regulation ofPD-L1 in CD11c+ Cells

Award Number: R01CA225108
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/04/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Metabolic Regulation ofPD-L1 in CD11c+ Cells - Project Summary/Abstract The long-term goal is to find better intervening approaches to interdict cancer initiation, progression and metastasis. The PD-L1/PD-1 signaling pathway is a critical immune checkpoint mechanism utilized by tumor to escape antitumor immune responses. PD-L1 binds to PD-1 on activated T cells to mediate an inhibitory signal through PD-1-expressing T cells. In comparison, the functional roles of PD-L1 expression in the myeloid compartment are less clear. CD11c+ DCs are well known for their function to capture tumor antigens and cross-present these antigens to T cells in tumor-draining lymph nodes, resulting in the generation of tumor-specific cytotoxic T lymphocytes (CTLs) that contribute to tumor rejection. Interestingly, we have shown that CD11c+ cells isolated from the blood of lysosomal acid lipase (LAL) knockout (lal-/-) mice possess immunosuppression in the absence of antigen presentation, and directly stimulate tumor proliferation in vitro and tumor growth in vivo. Concomitantly, PD-L1 expression was increased in lal-/- CD11c+ cells, which is required for immunosuppression and tumor stimulation. Our observations suggest that the LAL deficiency-induced metabolic switch leads CD11c+ cells to confer tumor stimulation rather than rejection. Based on these observations, this proposal will focus on how PD-L1 expression in lal-/- CD11c+ cells contributes to immune suppression and tumor stimulation during LAL-deficiency. LAL is a key enzyme that hydrolyzes cholesteryl esters and triglycerides in the lysosome of cells to generate free fatty acids (FFAs) and cholesterol. The metabolites of FFAs are ligands for nuclear transcription factor peroxisome proliferator activated receptor  (PPAR), a negative regulator of inflammation. Since LAL is critically involved in fatty acid metabolism, the proposed study will further elucidate the underneath metabolic mechanism by which lal-/- CD11c+ cells influence tumor immunity and stimulation through PD-L1 expression. RNAseq and flow cytometry demonstrated that PD-L1 expression is regulated by glucose/glutamine metabolic processes and mammalian target of rapamycin (mTOR) in lal-/- CD11c+ cells, which is under the control of PPAR. Therefore, the current proposal will test a central hypothesis that LAL/PPAR/mTOR axis-regulated PD-L1 expression plays a key role in lal-/- CD11c+ cells’ immune suppression and tumor stimulation through metabolic reprogramming. To achieve our goals, we will use the unique lal-/- mouse model and the conditional c-fms-rtTA/(TetO)7-CMV-hLAL;lal-/- triple mouse model (c-fms-Tg/KO) in which hLAL is specifically expressed in the myeloid compartment of lal-/- mice. The following specific aims are designed to test the central hypothesis:1) Characterizing the developmental and metabolic regulation of PD-L1 expression in CD11c+ cells; 2) Characterizing PD-L1 expression of CD11c+ cells in regulating T cell proliferation and functions; 3) Characterizing PD-L1 expression of CD11c+ cells in tumor stimulation. The successful outcome will help to design a more efficient regimen to increase the efficacy of PD-L1 cancer immunotherapy by manipulating the metabolic pathway and the immune checkpoint pathway.


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 = $0 )
2025	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	5	3/28/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2023 ( Subtotal = $520,593 )
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	5	3/15/2023	NON-COMPETING CONTINUATION	$42,496
2023	2023	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	5	11/10/2022	NON-COMPETING CONTINUATION	$478,097
														Subtotal = $520,593

Issue Date FY: 2022 ( Subtotal = $520,593 )
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	4	5/10/2022	NON-COMPETING CONTINUATION	$42,495
2022	2022	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	4	12/1/2021	NON-COMPETING CONTINUATION	$478,098
														Subtotal = $520,593

Issue Date FY: 2021 ( Subtotal = $531,218 )
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	3	2/2/2021	NON-COMPETING CONTINUATION	$26,562
2021	2021	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	3	11/18/2020	NON-COMPETING CONTINUATION	$504,656
														Subtotal = $531,218

Issue Date FY: 2020 ( Subtotal = $531,218 )
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	2	11/8/2019	NON-COMPETING CONTINUATION	$478,098
2020	2020	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	001	2	1/14/2020	NON-COMPETING CONTINUATION	$53,120
														Subtotal = $531,218

Issue Date FY: 2019 ( Subtotal = $547,418 )
2019	2019	TRUSTEES OF INDIANA UNIVERSITY	980 INDIANA AVE RM 2232	INDIANAPOLIS	IN	46202	MARION	USA	Cancer Biology Research	000	1	12/4/2018	NEW	$547,418
														Subtotal = $547,418

Grand Total All Awards = $2,651,040

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Metabolic Regulation ofPD-L1 in CD11c+ Cells

Award Number: R01CA225108

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/04/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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