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Reprogramming Antigen Presenting Cells in Lymph Nodes to Overcome Tumor Immune Tolerance

Award Number: F32CA281087
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 02/28/2027

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Reprogramming Antigen Presenting Cells in Lymph Nodes to Overcome Tumor Immune Tolerance - Abstract: Most cancer-related deaths are a consequence of metastatic disease. Yet, our understanding of the underlying mechanisms responsible for metastasis—especially the immune system's role in modulating metastatic progression—remains rudimentary. My sponsor’s lab recently discovered that tumor invasion into lymph nodes (LNs) evokes the induction of regulatory T cells (Tregs) that confers systemic, tumor-specific immune tolerance, thereby permitting distant (organ) metastases. While both human and murine tumor-involved lymph node tissues have demonstrated a conserved and dominant mechanism requiring Tregs for metastatic progression, the underlying mediator that governs their development remains enigmatic, and thus, warrants further investigation. In line with the notion that professional antigen-presenting cells (APCs) are critical for antigen-specific T cell development, my preliminary work revealed that professional APCs are differentially enriched in tumor-involved lymph nodes of mice. However, which APC population is responsible for promoting tumor-specific Treg development, and whether the tumor immune tolerance machinery can be therapeutically overcome remains to be investigated. To address these gaps in knowledge, I propose the following aims: 1) identify the APCs that potentiate LN metastasis-induced tumor-specific immune tolerance; and 2) assess therapeutic strategies that reprogram APCs to curtail metastatic progression. Using high-dimensional multiplexed imaging (CODEX), single-cell RNA-sequencing, various in vivo cell-depletion mouse models and adoptive cell transfer assays, as well as in vitro co-culture experiments, I will systematically dissect the key APC population that I hypothesize is responsible for mediating tumor-specific Treg development. To therapeutically reprogram the APCs away from tolerance induction, I will develop immunostimulatory antibody conjugates that drain into LNs and test them in mouse models of melanoma and pancreatic ductal adenocarcinoma. The proposed work aims to delineate the APC population that is responsible for mediating tumor-specific Treg induction and to advance the development of immunotherapeutic strategies to treat metastatic disease.


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 = $79,348 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	3	2/5/2026	NON-COMPETING CONTINUATION	$78,040
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	3	4/16/2026	NON-COMPETING CONTINUATION	$1,308
														Subtotal = $79,348

Issue Date FY: 2025 ( Subtotal = $75,520 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	2	2/13/2025	NON-COMPETING CONTINUATION	$74,284
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	2	5/22/2025	NON-COMPETING CONTINUATION	$1,236
														Subtotal = $75,520

Issue Date FY: 2024 ( Subtotal = $73,828 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	000	1	2/22/2024	NEW	$69,080
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	001	1	2/22/2024	NEW	$0
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Cancer Research Manpower	002	1	5/7/2024	NEW	$4,748
														Subtotal = $73,828

Grand Total All Awards = $228,696

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Reprogramming Antigen Presenting Cells in Lymph Nodes to Overcome Tumor Immune Tolerance

Award Number: F32CA281087

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 02/28/2027

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