# Investigating T Cell Egress via Lymphatic Vessels in Melanoma

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2022 · $387,731

## Abstract

Project Summary
The clinical efficacy of immune checkpoint blockade (ICB) in a subset of metastatic melanoma patients has
catalyzed a revolution in cancer care leading to its application to a variety of other tumor types. The
discrepancy in response to ICB between, and even within, tumor types, however, indicates that additional
mechanisms of suppression must be targeted to expand utility of these therapies. Recent biomarker studies,
indicate that presence of cytotoxic T cells (CTLs) within tumor microenvironments enriches for patients who are
likely to respond, suggesting that efforts to improve intratumoral accumulation of tumor-specific CTLs might
enhance response to therapy. The current proposal will examine mechanisms regulating T cell exit from
melanoma and propose inhibition of egress as a novel strategy to improve T cell retention and thus response
to ICB. We will test the hypothesis that tumor-associated lymphatic vessels influence intratumoral CTL pools
by directing their egress. Transgenic mice expressing a photoconvertible protein will be used to in situ label
and in vivo track tumor resident lymphocyte populations. Using this model system paired with transgenic T
cells and altered antigen ligands, we will determine the role antigen encounter plays in determining which cells
egress from melanoma microenvironments to delineate how T cell egress from tumors contributes to the
diversity of the intratumoral T cell repertoire. Our preliminary data indicates that T cells specific for tumor
antigens egress from tumors indicating that inhibition of tumor exit, to retain these T cells, might improve
response to immunotherapy. To test this, we will determine the functional significance of candidate chemokine
receptors, CXCR4 and CXCR6, which we predict regulate T cell egress and retention respectively. We will
determine the therapeutic synergy of combining agents targeting these pathways with immune checkpoint
blockade. Finally, we have shown that disrupting lymphatic vessel crosstalk with CTLs, mediated by IFNγ,
improves tumor control. We will explore the role of IFNγ-mediated bidirectional crosstalk in regulating T cell
egress through lymphatic vessels and thus propose T cell egress as a mechanism of immune resolution
coopted by tumor microenvironments to mediate immune evasion. Taken all together, we propose that CTLs
integrate multiple signals in melanoma microenvironments that tune their accumulation and function in concert
with the lymphatic vasculature. We predict that inhibition of CTL egress represents a tractable clinical strategy
that can synergize with therapies targeting additional immunosuppressive mechanisms (e.g. metabolism and
exhaustion), and mechanistic studies described herein will provide the rationale for future clinical translation.

## Key facts

- **NIH application ID:** 10334541
- **Project number:** 5R01CA238163-04
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** Amanda W. Lund
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $387,731
- **Award type:** 5
- **Project period:** 2020-03-01 → 2024-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10334541

## Citation

> US National Institutes of Health, RePORTER application 10334541, Investigating T Cell Egress via Lymphatic Vessels in Melanoma (5R01CA238163-04). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10334541. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*