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Rewiring the myeloid cell response to adjuvants to improve tumor control

Award Number: R01CA244142
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/02/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Rewiring the myeloid cell response to adjuvants to improve tumor control - The critical preliminary data for this proposal is that contrary to the accepted dogma, following exposure to endogenous immune adjuvants MyD88 delivers a negative signal to macrophages that limits tumor control by radiation therapy. We demonstrate that in poorly immunogenic tumors, macrophages are rewired following exposure to dying cancer cells such that they suppress multiple features of the tumor immune environment. This includes the ability of T cells to control residual disease, and dendritic cell maturation. The aim of this proposal is to understand the mechanisms by which this suppression occurs, identify the regulation of macrophage suppression, and use this to identify patient populations that will respond poorly to current therapies. We hypothesize that exposure to dying cells rewires macrophage signaling such that innate activation of MyD88 suppresses local tumor immunity. The specific aims of this study are to 1: Test the hypothesis that loss of MyD88 prevents NFKB driven-anti-inflammatory gene transcription and results in increased IRF3 driven IFN transcription; 2: Test the hypothesis that signaling through Mertk-mediated ‘rewiring’ of macrophages changes the response to adjuvants limiting immune function in the tumor environment; and 3: Test the hypothesis that MyD88 patterns of gene expression are linked to poor patient outcome. Our study design incorporates CT-guided radiation therapy of multiple authentic pancreatic tumor models and using a range of RT doses and fractionations. These are combined with unique knockouts and assays that allow us to identify divergent myeloid responses in vitro and in vivo. Our analyses of clinical samples use high quality bioinformatic approaches that allow us to evaluate effect of the tumor environment on the biological response to innate adjuvants in patient samples.


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 = -$22,228 )
2025	2024	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	5	5/5/2025	NON-COMPETING CONTINUATION	-$22,228
														Subtotal = -$22,228

Issue Date FY: 2024 ( Subtotal = $358,566 )
2024	2024	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	001	5	5/3/2024	NON-COMPETING CONTINUATION	$18,872
2024	2024	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	5	11/29/2023	NON-COMPETING CONTINUATION	$339,694
														Subtotal = $358,566

Issue Date FY: 2023 ( Subtotal = $369,889 )
2023	2023	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	001	4	3/17/2023	NON-COMPETING CONTINUATION	$30,195
2023	2023	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	4	11/29/2022	NON-COMPETING CONTINUATION	$339,694
														Subtotal = $369,889

Issue Date FY: 2022 ( Subtotal = $369,889 )
2022	2022	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	001	3	5/24/2022	NON-COMPETING CONTINUATION	$30,195
2022	2022	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	3	12/3/2021	NON-COMPETING CONTINUATION	$339,694
														Subtotal = $369,889

Issue Date FY: 2021 ( Subtotal = $377,438 )
2021	2021	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	001	2	2/11/2021	NON-COMPETING CONTINUATION	$18,873
2021	2021	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	2	11/18/2020	NON-COMPETING CONTINUATION	$358,565
														Subtotal = $377,438

Issue Date FY: 2020 ( Subtotal = $377,438 )
2020	2020	PROVIDENCE HEALTH & SERVICES - OREGON	4805 NE GLISAN ST	PORTLAND	OR	97213	MULTNOMAH	USA	Cancer Treatment Research	000	1	12/2/2019	NEW	$377,438
														Subtotal = $377,438

Grand Total All Awards = $1,830,992

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Rewiring the myeloid cell response to adjuvants to improve tumor control

Award Number: R01CA244142

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/02/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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