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Modeling Immune Cell Recruitment and its Impact on Triple Negative Breast Cancer Recurrence in the Irradiated Microenvironment

Award Number: F31CA254311
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 05/31/2023

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Modeling Immune Cell Recruitment and its Impact on Triple Negative Breast Cancer Recurrence in the Irradiated Microenvironment - PROJECT SUMMARY Approximately half of triple negative breast cancer (TNBC) patients receive breast conserving therapy, which includes irradiating the primary tumor site. Although this therapy improves prognosis overall, patients continue to experience locoregional recurrences at high rates. The mechanisms controlling recurrence following therapy are poorly understood. Previous research suggests that normal tissue radiation damage may be correlated to recurrence. Pre-clinical studies have shown that tumor cells migrate into irradiated mammary tissue and that macrophages play a critical role in the tumor cell recruitment process. While blockade of macrophage infiltration was shown to eliminate tumor cell migration to irradiated sites, the impact of macrophage phenotype has not been investigated. Macrophages with a wound healing phenotype (M2) are known to promote tumor growth and progression, but whether M2 macrophages influence tumor cell recruitment and proliferation in irradiated tissues is unknown. The central hypothesis of this proposal is that radiation damage in the tissue microenvironment promotes a pre-metastatic niche through immunosuppressive cell infiltration. I will test this hypothesis using pre- clinical orthotopic breast cancer models as well as organoids to study the normal tissue response to radiation and its influence on recurrence. This project is guided by two specific aims: 1) To characterize macrophage phenotypes associated with RT- induced recurrence and 2) to identify targetable secreted factors that contribute to tumor cell recruitment in irradiated tissues. In Aim 1, I will rigorously examine the immune cell infiltrate into irradiated mammary tissue using flow cytometry. To confirm the importance of M2 macrophages in recurrence, I will develop an M2 macrophage-depleted mouse model by blocking polarization with small molecule inhibitors or monoclonal antibodies. Finally, I will determine the impact of M2 macrophage depletion on tumor cell recruitment to irradiated tissues. In Aim 2, I will use an organoid model developed by our laboratory that recapitulates pre-clinical observations. I will analyze secreted pro-tumor factors by co-culturing organoids with macrophages, tumor cells, and CD8+ T cells and characterizing secreted cytokines in conditioned media. I will then evaluate how these factors contribute to tumor cell recruitment in vivo. This study will establish the conditions that lead to recurrence following radiotherapy, including composition of macrophage infiltrate and mechanisms of tumor regrowth, which will have significant implications for TNBC patients vulnerable to recurrence.


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: 2024 ( Subtotal = -$18,751 )
2024	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	000	3	1/3/2024	NON-COMPETING CONTINUATION	-$18,439
2024	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	001	3	3/22/2024	NON-COMPETING CONTINUATION	-$312
														Subtotal = -$18,751

Issue Date FY: 2023 ( Subtotal = $31,820 )
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	001	3	5/22/2023	NON-COMPETING CONTINUATION	$942
2023	2023	VANDERBILT UNIVERSITY	110 21ST AVE S	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	000	3	12/22/2022	NON-COMPETING CONTINUATION	$30,878
														Subtotal = $31,820

Issue Date FY: 2022 ( Subtotal = $30,878 )
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	000	2	2/16/2022	NON-COMPETING CONTINUATION	$30,162
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	001	2	5/13/2022	NON-COMPETING CONTINUATION	$717
2022	2022	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	002	2	8/12/2022	NON-COMPETING CONTINUATION	-$1
														Subtotal = $30,878

Issue Date FY: 2021 ( Subtotal = $34,064 )
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	000	1	12/17/2020	NEW	$33,548
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	001	1	12/17/2020	NEW	$0
2021	2021	VANDERBILT UNIVERSITY, THE	110 21ST AVENUE S STE 800	NASHVILLE	TN	37203	DAVIDSON	USA	Cancer Research Manpower	002	1	2/3/2021	NEW	$516
														Subtotal = $34,064

Grand Total All Awards = $78,011

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Modeling Immune Cell Recruitment and its Impact on Triple Negative Breast Cancer Recurrence in the Irradiated Microenvironment

Award Number: F31CA254311

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 05/31/2023

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