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Stress-induced immunosuppression via downregulation of interferon in triple negative breast cancer

Award Number: K08CA279766
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2024
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Stress-induced immunosuppression via downregulation of interferon in triple negative breast cancer - Triple negative breast cancer (TNBC) is the most aggressive form of breast cancer (BC) which occurs more frequently in younger women, often diagnosed once the disease has already metastasized. It is the only BC subtype where immune checkpoint inhibitors (ICIs) are approved for use, but only a small number of patients respond to current ICI treatments. One mechanism of resistance is low expression of intratumural chemokines CXCL9 and CXCL10, essential for attracting anti-tumor CD8+ T cells into the tumor microenvironment (TME). Psychosocial stress, experienced by many BC patients can enhance immunosuppression. β-adrenergic receptor blockade has shown higher survival benefit in TNBC patients compared with other BC subtypes (observational studies), suggesting a possibility of sympathetic overdrive in TNBC. However, the mechanistic role of psychosocial stress in treatment resistance to ICIs among TNBC patients remains unknown. We have shown that chronic stress and its mediators, epinephrine (EPI) and norepinephrine (NE), drive immunosuppression in the TME by decreasing CD8+ T cells and increasing myeloid derived suppressor cells and regulatory T cells. Our subsequent study showed that propranolol, a pan-β-blocker, improves response to ICIs in metastatic melanoma patients. We also found that EPI can mediate the induction of prostaglandin E2 (PGE2) in BC tissues. We and others have shown that PGE2 inhibits interferon (IFN)-induced CXCL9/10 secretion. Thus, I hypothesize that chronic stress promotes immunosuppression in TNBC by increasing PGE2 and inhibiting IFN pathways, resulting in decreased CXCL9/10. I propose to test this hypothesis in the following aims: 1) Examine NE-induced changes in TNBC tissues and test therapeutic measures ex vivo; 2) Study immune changes in pre- vs. post-treatment tumor tissues and blood of metastatic TNBC patients receiving propranolol and ICI; and 3) Correlate validated measures of psychosocial stress with the expression of IFNs and CXCL9/10 in BC tissues. To achieve these goals, I will utilize TNBC tissues from patients in ex vivo studies, conduct a prospective clinical trial, and examine relationships between self-reported stress and correlates of tumor immunity in banked samples. To gain mechanistic understanding, complementary state-of-the-art multiplex tissue imaging techniques including confocal microscopy, imaging mass cytometry, and spatial transcriptomics will be utilized. Completion of the proposed work will provide key novel insights into the mechanistic role of the PGE2-IFN-chemokines pathway in stress-induced TME immunosuppression and help inform new approaches that will be translated into enhanced therapeutic benefit for TNBC patients. This project will advance my development into an independent clinical scientist and translational researcher advancing precision immuno-oncology treatments for TNBC. This will be accomplished in a rich academic environment at Emory University School of Medicine under the guidance of an outstanding mentorship team with complementary expertise in the areas of breast cancer, immuno-oncology, TME-associated chemokines, prostaglandins, IFNs, and psychosocial stress.


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: 2026 ( Subtotal = $300,357 )
2026	2026	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Research Manpower	000	4	6/23/2026	NON-COMPETING CONTINUATION	$300,357
														Subtotal = $300,357

Issue Date FY: 2025 ( Subtotal = $300,357 )
2025	2025	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Research Manpower	003	3	6/23/2025	NON-COMPETING CONTINUATION	$300,357
2025	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	002	1	6/17/2025	NEW	$0
2025	2024	EMORY UNIVERSITY	201 DOWMAN DR NE	ATLANTA	GA	30322	DEKALB	USA	Cancer Research Manpower	001	2	5/19/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$156,562
2025	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	000	1	5/19/2025	NEW	-$156,562
														Subtotal = $300,357

Issue Date FY: 2024 ( Subtotal = $314,333 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	001	1	6/3/2024	NEW	$290
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Research Manpower	000	1	5/31/2024	NEW	$314,043
														Subtotal = $314,333

Grand Total All Awards = $915,047

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Stress-induced immunosuppression via downregulation of interferon in triple negative breast cancer

Award Number: K08CA279766

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2024

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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