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Dissecting Molecular Mechanisms of Tumor-Induced Myeloid-Mediated Immune Suppression in Triple-Negative Breast Cancer

Award Number: R01CA287731
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/13/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2029

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Dissecting Molecular Mechanisms of Tumor-Induced Myeloid-Mediated Immune Suppression in Triple-Negative Breast Cancer - PROJECT SUMMARY Breast cancer remains the leading cause of cancer-related mortality in women worldwide. Despite considerable progress in the treatment of early-stage disease, a significant frequency of patients will develop recurrence with distant metastases. Triple-negative breast cancer (TNBC) is the most aggressive subtype with a dismal prognosis; it lacks the estrogen receptor, progesterone receptor, and HER2 expression and, therefore, is resistant to treatments targeting those pathways. Interestingly, harnessing the immune system through immunotherapy with immune checkpoint inhibitors (ICIs) has improved survival rates; albeit modestly, when used in combination with standard-of-care chemotherapy. Thus, TNBC remains a neoplastic disease with unmet clinical challenges. New preliminary data in our laboratories indicate that loss-of-function of TAZ, the key component in the Hippo signaling pathway, inhibits tumor progression in mouse models of TNBC in immune competent, but not immune deficient mice, indicating that tumor TAZ expression plays an underappreciated extrinsic role in TNBC biology. Mass cytometry analysis suggested that tumor TAZ expression acts extrinsically to regulate the recruitment and/or function of myeloid-derived suppressor cells (MDSCs) and, perhaps, tumor- associated macrophages (TAMs), and regulatory T cells (Tregs). Additional mechanistic studies showed that TAZ knockdown in preclinical TNBC models led to a reduction in MDSCs, as well as a reduction in the expression of several cytokines/chemokines, particularly CCL20, potentially linked to the mobilization of MDSCs. Thus, these findings implicated a previously unrecognized biology of tumor-intrinsic TAZ expression in regulating TNBC progression via its actions on the immune-tumor microenvironment (TME), notably MDSC trafficking. The overall objectives of this proposal are to understand the underlying molecular mechanisms by which TAZ expression regulates the accumulation of immune suppressive cells like MDSCs in the TME of TNBC. Our central hypothesis is that TAZ expression in TNBC regulates the TME landscape via cancer cell non-autonomous-driven mechanisms. Our long-term goals are to decipher the crosstalk between TAZ expression in TNBC and the immune contexture of the TME to uncover new prognostic or therapeutic targets in TNBC biology. To achieve these goals, we propose the following three aims: 1) determine the impact of tumor-intrinsic TAZ expression on the immune-tumor microenvironment in preclinical models of TNBC; 2) determine the molecular mechanisms by which tumor-intrinsic TAZ expression recruits MDSCs to the TME; and 3) determine the relationship between tumor TAZ expression and the immune-tumor microenvironment in patients with TNBC. A major impact of this study is to identify previously undescribed TAZ-mediated mechanisms that will unveil new biomarkers or inform novel therapeutic interventions for advanced or metastatic TNBC.


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 = $558,523 )
2025	2025	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Biology Research	000	2	8/20/2025	NON-COMPETING CONTINUATION	$558,523
														Subtotal = $558,523

Issue Date FY: 2024 ( Subtotal = $571,496 )
2024	2024	UNIVERSITY OF TOLEDO	3000 ARLINGTON AVE	TOLEDO	OH	43614	LUCAS	USA	Cancer Biology Research	000	1	9/13/2024	NEW	$571,496
														Subtotal = $571,496

Grand Total All Awards = $1,130,019

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Dissecting Molecular Mechanisms of Tumor-Induced Myeloid-Mediated Immune Suppression in Triple-Negative Breast Cancer

Award Number: R01CA287731

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/13/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2029

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