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The Induction of Macrophage Endoplasmic Reticulum Stress by Irradiated-Tumor Derived Extracellular Vesicles Supports the Adoption of a Pro-Tumor Phenotype

Award Number: F30CA239564
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

Group Awards By Issue Date FY or Funding FY:

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Project Summary Radiotherapy initiates the recruitment of alternatively stimulated (M2) macrophages to the tumor microenvironment. These cells exhibit a “pro-tumor phenotype,” stimulating angiogenesis, suppressing anti- tumor immunity, and enhancing tumor cell radioresistence. This limits the overall efficacy of radiotherapy for solid tumors such as non-small cell lung cancer. Current research in the field of radioimmunology is focused on manipulations that either inhibit the recruitment of these cells or that alter their behavior once they reach the tumor microenvironment. However, exactly how irradiated cancer cells manipulate macrophages is largely unknown. We have discovered that extracellular vesicles elaborated by irradiated lung cancer cells (IR-EVs) induce ER-stress and elicit the production of “pro-tumor” cytokines from macrophages in an SRA/CD204 dependent manner. The overall objective of this project is to define the molecular mechanisms by which IR-EVs induce macrophage pro-tumor cytokine expression. First, we will test the functional impact of IR-EV induced macrophage ER stress on macrophage phenotype using CHOP-/- C57BL/6 mice and soluble inhibitors of ER stress. Then, we will investigate the role of macrophage SRA/CD204 in the response of macrophages to IR-EVs. We will do this using SRA/CD204-/- C57BL/6 mice as well as a novel SRA/CD204 blocking antibody developed in our laboratory. Finally, we will compare the circulating IR-EVs of recurrent and non-recurrent non-small cell lung cancer patients to determine if they can predict the outcome of radiotherapy. EVs from recurrent and non- recurrent NSCLC patients isolated before, during, and after RT will be assessed for their ability to stimulate a pro-tumor macrophage phenotype in vitro. Then, mass spectrometry will be used to identify a potential SRA/CD204 binding protein upregulated on the surface of IR-EVs from patients and cultured cells. The potential of ligand bearing exosomes to segregate lung cancer patients into relapse or disease-free survival groups will be evaluated using a commercially available ELISA on concentrated serum exosomes.


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: 2023 ( Subtotal = $40,355 )
2023	2023	VIRGINIA COMMONWEALTH UNIVERSITY	910 WEST FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	000	5	4/20/2023	NON-COMPETING CONTINUATION	$40,355
														Subtotal = $40,355

Issue Date FY: 2022 ( Subtotal = $39,413 )
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	002	4	8/12/2022	NON-COMPETING CONTINUATION	-$1
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	000	4	4/20/2022	NON-COMPETING CONTINUATION	$30,753
2022	2022	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	001	4	5/18/2022	NON-COMPETING CONTINUATION	$8,661
														Subtotal = $39,413

Issue Date FY: 2021 ( Subtotal = $38,697 )
2021	2021	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	000	3	4/7/2021	NON-COMPETING CONTINUATION	$38,697
														Subtotal = $38,697

Issue Date FY: 2020 ( Subtotal = $38,181 )
2020	2020	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	000	2	3/27/2020	NON-COMPETING CONTINUATION	$38,181
														Subtotal = $38,181

Issue Date FY: 2019 ( Subtotal = $37,677 )
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	000	1	4/26/2019	NEW	$37,677
2019	2019	VIRGINIA COMMONWEALTH UNIVERSITY	912 W FRANKLIN ST	RICHMOND	VA	23284	RICHMOND CITY	USA	Cancer Research Manpower	001	1	4/26/2019	NEW	$0
														Subtotal = $37,677

Grand Total All Awards = $194,323

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The Induction of Macrophage Endoplasmic Reticulum Stress by Irradiated-Tumor Derived Extracellular Vesicles Supports the Adoption of a Pro-Tumor Phenotype

Award Number: F30CA239564

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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