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Mechanisms of Lymphatic Metastasis in Pancreatic Ductal Adenocarcinoma

Award Number: F30CA281080
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/01/2025
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Mechanisms of Lymphatic Metastasis in Pancreatic Ductal Adenocarcinoma - ABSTRACT Distant metastasis is the primary cause of cancer-related death and is generally preceded by metastasis to the lymph node (LN). Since lymph nodes serve as staging grounds for anti-tumor immunity, their high susceptibility to metastatic colonization has been considered a paradox. To date, it has been thought that for tumor cells to survive in the draining lymph node, it must first be preconditioned by extrinsic, tumor-derived, factors towards a state of immune-suppression. Whether intrinsic qualities of the lymph node may also impede its immune response to metastasizing tumor cells is not known. My thesis work to date has identified an intrinsic basis for early lymph node metastasis, independent of preconditioning, linked to the lymph node’s large regulatory T cell (Treg) population. Using murine cancer cell lines that express an antigen, we find that tumor-specific CD8 T cells exhibit markedly lower cytotoxicity in lymph nodes than in circulating blood. T cell depletion greatly enhanced hematogenous metastasis to the lungs but not lymphatic metastasis to regional lymph nodes. Direct injection of parental tumor cells into the lymph node and blood formed tumors at a similar rate in the lymph node and lungs, respectively, but forced expression of antigen conferred a marked growth advantage following intra-lymph node injection. This advantage was dependent upon regulatory T cells, which locally suppressed the cytotoxicity of tumor-specific CD8 T cells in the lymph node to permit tumor growth. Based on my preliminary findings, depleting Tregs is an attractive therapeutic strategy for treating LN metastasis. However, systemic and continuous depletion of Tregs leads to autoimmunity and eventual death. In Aim 1 I will Investigate transient, single LN Treg depletion as a therapeutic strategy to treat LN metastasis. As LNs promote anti-tumor immune responses by facilitating priming events, an accumulation of tumor cells in the LN could represent an opportunity for increased antigen uptake and priming. Consistently, my preliminary data suggests that metastatic LNs have many more antigen-carrying DCs than non-metastatic draining LNs. However, the antigen-carrying DCs in tumor-bearing LNs are significantly suppressed, expressing very low levels of co-stimulatory molecules. As Tregs also accumulate during LN metastasis, I hypothesize that Tregs prevent effective anti-tumor priming by suppressing co-stimulatory molecule expression on tumor-antigen carrying cDC1s. In Aim 2 I will determine whether Tregs suppress anti-tumor CD8 T cell priming in the lymph node by suppressing co-stimulatory molecule expression on tumor antigen-carrying DCs or by preventing antigen stimulation. I hypothesize that transient depletion of regulatory T cells in a single metastatic LN will restore anti-tumor CD8, priming and cytotoxicity and effectively eradicate LN metastasis.


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 = $7,787 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	2	3/19/2026	NON-COMPETING CONTINUATION	$7,787
														Subtotal = $7,787

Issue Date FY: 2025 ( Subtotal = $37,226 )
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	001	1	3/10/2025	NEW	$0
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	000	1	3/10/2025	NEW	$36,662
2025	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Research Manpower	002	1	5/22/2025	NEW	$564
														Subtotal = $37,226

Grand Total All Awards = $45,013

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Mechanisms of Lymphatic Metastasis in Pancreatic Ductal Adenocarcinoma

Award Number: F30CA281080

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/01/2025

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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