Mechanisms of lymphatic metastasis in pancreatic ductal adenocarcinoma

The National Cancer Institute awarded The Trustees of The University of Pennsylvania $126,220 on September 10, 2025, under the Cancer Research Manpower program (CFDA 93.398) to support research into mechanisms of lymphatic metastasis in pancreatic ductal adenocarcinoma.

The funded work investigates the intrinsic basis for early lymph node metastasis independent of tumor-derived preconditioning, with focus on the role of regulatory T cells (Tregs) in suppressing anti-tumor CD8 T cell cytotoxicity within lymph nodes. Preliminary findings link a large Treg population in lymph nodes to tumor cell survival. The research proposes transient, single lymph node Treg depletion as a therapeutic strategy to treat lymph node metastasis while avoiding the autoimmunity and death associated with systemic continuous Treg depletion.

Performance occurs at the University of Pennsylvania in Philadelphia, Pennsylvania, with a period of performance through May 31, 2026. The award is classified as a Project Grant.

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.