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The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development

Award Number: R01CA190449
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2015
PERIOD OF PERFORMANCE END DATE: 04/30/2021

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The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development - Project Summary Tumor-driven myeloid-derived suppressor cell (MDSC) expansion in the marginal zone (MZ) of the spleen is critical for suppression of anti-tumor CD8+ T cell responses in vivo. In previously published data we reported that marginal zone-resident macrophages (MZ MΦs) are critical sensors for cellular debris in circulation driving early tolerogenic responses and preventing auto-immunity. When we examined the spleens of tumor- bearing mice we found significant expansion of MDSCs in the MZ in contact with MZ MΦs. Deletion of MZ MΦs abrogated tumor-induced splenic IL-6 and CCL2 expression and MDSC expansion suggesting a previously unknown mechanistic relationship between MZ MΦs and MDSCs. Moreover, we found MDSC activation induced differentiation and suppression required engagement of the GCN2 arm of the integrated stress response which, in turn, drove expression of the myeloid differentiation factor C/EBPβ. In this proposal we hypothesize MZ MΦ-dependent expansion of MDSCs and GCN2-driven acquisition of suppressive function are related with MZ MΦs providing the early signals driving MDSC recruitment to the MZ and activation. Our project will examine how tumors impact MZ MΦ expression of pro-MDSC factors and determine the functional relationship between this and GCN2 signal activation in MDSC precursors. If successful, the findings from this project would provide new insight into the contribution of microenvironment and stromal macrophages in tumor-mediated suppressive processes as well as provide novel therapeutic targets for cancer immuno-therapy.


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: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON			CAN	Cancer Biology Research	000	6	10/13/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $239,637 )
2020	2020	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Cancer Biology Research	000	6	5/22/2020	NON-COMPETING CONTINUATION	$239,637
														Subtotal = $239,637

Issue Date FY: 2019 ( Subtotal = $1 )
2019	2019	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Cancer Biology Research	000	5	5/17/2019	NON-COMPETING CONTINUATION	$1
														Subtotal = $1

Issue Date FY: 2018 ( Subtotal = $247,050 )
2018	2018	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Cancer Biology Research	000	4	4/13/2018	NON-COMPETING CONTINUATION	$247,050
														Subtotal = $247,050

Issue Date FY: 2017 ( Subtotal = $247,050 )
2017	2017	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Cancer Biology Research	000	3	4/26/2017	NON-COMPETING CONTINUATION	$222,345
2017	2017	UNIVERSITY HEALTH NETWORK	200 ELIZABETH ST	TORONTO	ON	M5G 2C4		CAN	Cancer Biology Research	001	3	6/7/2017	NON-COMPETING CONTINUATION	$24,705
														Subtotal = $247,050

Issue Date FY: 2016 ( Subtotal = $247,050 )
2016	2016	UNIVERSITY HEALTH NETWORK	200 ELIZABETH STREET	TORONTO ONTARIO				CAN	Cancer Biology Research	001	2	6/2/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$247,050
2016	2015	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	1	5/26/2016	NEW	$0
														Subtotal = $247,050

Issue Date FY: 2015 ( Subtotal = $347,319 )
2015	2015	GEORGIA REGENTS RESEARCH INSTITUTE INC	1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Cancer Biology Research	000	1	4/7/2015	NEW	$347,319
														Subtotal = $347,319

Grand Total All Awards = $1,328,107

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The role of marginal zone macrophages and immuno-metabolism in tumor-driven MDSC development

Award Number: R01CA190449

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2015

PERIOD OF PERFORMANCE END DATE: 04/30/2021

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