# The influence of lymph node metastasis on local and systemic anti-tumor immunity

> **NIH NIH F30** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $41,614

## Abstract

PROJECT SUMMARY
Lymph node (LN) metastasis is a key negative prognostic factor in melanoma and other solid tumors. Recent
clinical trials in regionally advanced melanoma have suggested that complete LN dissection does not improve
survival outcomes, and that neoadjuvant therapy is efficacious. If the standard of care of regional disease evolves
to encompass these results, we will soon be treating many more patients with intact tumor-draining LN (tdLN),
both metastatic and non-metastatic. Consequently, it is essential we understand the therapeutic potential – or
liability – of the tdLN. While the LN has historically been considered a passive conduit for metastasis, recent
studies have illuminated the role of LN metastasis in promoting a state of systemic immunosuppression
permissive of distant metastasis. However, the specific mechanisms activated by LN metastasis that suppress
systemic immune surveillance are poorly understood. We have generated a comprehensive spatiotemporal map
of lymph node remodeling during metastasis using paired single cell and spatial transcriptomic data in an
inducible BrafV600E; Pten-/- cutaneous melanoma model that spontaneously metastasizes to the tdLN. Integrated
preliminary analysis of this multimodal transcriptional data suggests that effective anti-tumor immune
surveillance is dependent on production of the alarmin IL-33 by lymphatic endothelial cells (LECs), which
activates mast cells to produce tumor necrosis factor (TNF). TNF can support many inflammatory processes; in
our data, appears to be essential for maintaining natural killer (NK) cell activation and proliferation. Here, we test
the hypothesis that LEC-derived IL-33 is essential for maintaining local immune surveillance against LN
metastasis. In Aim 1, we validate our transcriptional data and investigate the proposed niche through imaging
colocalization and flow cytometry analysis of metastatic tdLN and tdLN that lack TNF or IL-33 production. In Aim
2, we interrogate the relationship between IL-33 production and local and systemic anti-tumor immune
surveillance through assays that quantify lung and LN metastatic burden. In Aim 3, we correlate the expression
of IL-33 with human LN metastasis. Additionally, we analyze human metastatic LN from patients with cutaneous
melanoma to corroborate that this signaling network may be relevant to human metastatic progression.
Collectively, this work will provide a comprehensive understanding of the immunological changes occurring in
the tdLN and outline the role of IL-33 in local and systemic immune surveillance. Completion of this proposal will
provide me an extensive training in translational tumor immunology and specific opportunities to improve my
skills in computational analysis, scientific communication, and mentorship. This training will directly prepare me
for a career as an independent investigator and clinical oncologist at a major academic cancer center. My training
objectives are supported by my sponsor (Dr...

## Key facts

- **NIH application ID:** 10996877
- **Project number:** 1F30CA288142-01A1
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Katherine Ventre
- **Activity code:** F30 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $41,614
- **Award type:** 1
- **Project period:** 2024-08-01 → 2027-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10996877

## Citation

> US National Institutes of Health, RePORTER application 10996877, The influence of lymph node metastasis on local and systemic anti-tumor immunity (1F30CA288142-01A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10996877. Licensed CC0.

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