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Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid

Award Number: R37CA234027
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/03/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid - Project Summary and Abstract Evading immune responses is a hallmark of cancer. Solid tumors create a microenvironment that prevent detection of tumor cells by the immune system and block anti-tumor T cell activity. The therapeutic value of targeting immune evasion pathways is highlighted by the recent clinical successes of alleviating T cell suppression via immune checkpoint blockade in a handful of solid tumors. However, anti-tumor T cells are not generated in most solid tumors, which greatly limits the application of checkpoint blockade. One reason for this is the paucity and dysfunction of antigen-presenting dendritic cells (APCs) in solid tumor microenvironment (TME), but the underlying pathways are poorly understood. Our long-term goal is to discover and delineate pathways that control APC recruitment, differentiation, and function in TME. The overarching goal is to target these pathways to enhance antigen presentation and adaptive immune responses for solid tumor immunotherapy. I have previously developed powerful genetically engineered mouse models of sarcomas, a type of lethal solid tumor, as well as murine models to study antigen-presenting cells. Using these tools, we have recently discovered that retinoic acid (RA) produced by tumor cells act on tumor-infiltrating monocytes to prevent their differential into dendritic cells, instead promoting their differentiation into immunosuppressive macrophages. Furthermore, we have found that the cytokine IL13 promotes RA production in tumor cells. Based on these findings, our central hypothesis is that IL13-induced RA production by tumor cells prevents the generation of monocyte-derived dendritic cells in TME. Our three specific aims will; delineate the mechanism by which RA affects monocyte differentiation and antigen presentation (Aim 1), uncover the source of IL13 in TME and its impact on anti-tumor immune responses (Aim 2), and examine the potential of targeting IL13 and RA signaling for tumor immunotherapy (Aim 3). This work will have significant impact on our understanding of immunomodulation in solid tumors and extend our understanding of how tissue metabolites can control monocyte differentiation. Our findings will also open new avenues for solid tumor immunotherapy based on targeting RA signaling and APCs. The clinical implications are particularly impactful for sarcomas where current treatment options are extremely limited. Our work is innovative because it will open new avenues of research examining the role of retinoid signaling in APC differentiation and tumor immunity. There are many commercially available small molecule inhibitors of RA signaling, but none has been used for therapeutic purposes. Therefore, our work will not only provide a proof of concept for RA blockade in tumor immunotherapy, but is also amenable to rapid human translation.


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 = $367,066 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	7	11/14/2024	NON-COMPETING CONTINUATION	$330,360
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	003	7	5/29/2025	NON-COMPETING CONTINUATION	$36,706
2025	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	6	3/14/2025	EXTENSION WITH OR WITHOUT FUNDS	$14,894
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	5	3/14/2025	NON-COMPETING CONTINUATION	-$14,894
														Subtotal = $367,066

Issue Date FY: 2024 ( Subtotal = $353,132 )
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	6	2/21/2024	EXTENSION WITH OR WITHOUT FUNDS	$334,549
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	6	9/24/2024	EXTENSION WITH OR WITHOUT FUNDS	$0
2024	2024	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	6	8/1/2024	EXTENSION WITH OR WITHOUT FUNDS	$18,583
														Subtotal = $353,132

Issue Date FY: 2023 ( Subtotal = $360,922 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	5	3/17/2023	NON-COMPETING CONTINUATION	$29,463
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	5	11/8/2022	NON-COMPETING CONTINUATION	$331,459
														Subtotal = $360,922

Issue Date FY: 2022 ( Subtotal = $368,288 )
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	4	11/11/2021	NON-COMPETING CONTINUATION	$331,459
2022	2022	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	4	5/25/2022	NON-COMPETING CONTINUATION	$36,829
														Subtotal = $368,288

Issue Date FY: 2021 ( Subtotal = $368,288 )
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	3	1/22/2021	NON-COMPETING CONTINUATION	$18,415
2021	2021	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	3	11/23/2020	NON-COMPETING CONTINUATION	$349,873
														Subtotal = $368,288

Issue Date FY: 2020 ( Subtotal = $368,288 )
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	2	11/5/2019	NON-COMPETING CONTINUATION	$331,459
2020	2020	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	2	1/14/2020	NON-COMPETING CONTINUATION	$36,829
														Subtotal = $368,288

Issue Date FY: 2019 ( Subtotal = $368,288 )
2019	2019	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	12/3/2018	NEW	$368,288
														Subtotal = $368,288

Grand Total All Awards = $2,554,272

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Regulation of antigen presenting cells in the tumor microenvironment by retinoic acid

Award Number: R37CA234027

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/03/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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