# Targeting the Regulation of High Endothelial Venules in HNSCC Regional Recurrence

> **NIH NIH F31** · UNIVERSITY OF COLORADO DENVER · 2024 · $43,374

## Abstract

Abstract
Head and Neck Squamous Cell Carcinoma (HNSCC) is a deadly disease with proclivity for regional spread to
the lymphatic chains following definitive therapy (regional recurrence). This recurrent disease in the lymph
nodes remains a clinical burden that severely dampens overall survival, yet the biological underpinnings of this
phenomenon remain elusive. Our lab has shown in murine models of HNSCC that targeting
immunosuppressive T-regulatory cells (Tregs), prior to tumor inoculation rather than following, ablates regional
recurrence altogether. Mechanistically, we find that Tregs interfere with High Endothelial Venules (HEVs),
specialized postcapillary venules in the lymph node that allow for lymphocyte transmigration, early during
tumor development. This interference of HEVs leads to the engorgement and de-differentiation of HEV
structure, associated decreased lymphocyte trafficking and promotion of cancer cell quiescence. Indeed, we
find that quiescent cancer cells, measured by p27+ expression, uniquely occupy the perivascular niche (PVN)
surrounding the HEVs early during tumor progression suggesting that de-differentiated HEVs interact directly
with the cancer cells to promote regional recurrence. These data led us to believe that targeting HEV function
could prove to mitigate regional recurrence. We therefore sought to target HEV functioning during early tumor
formation by using an agonist for Lymphotoxin Beta Receptor (LtBR), which has been shown to restore
function of HEVs and increase lymphocyte presence within tumors. Upon addition of a systemic LtBR agonist
to therapeutic radiation and Treg depletion, we observed a striking reduction in regional recurrence and a
significant increase in lymphocyte presence within the tumor draining lymph node (tDLN), the site of regional
recurrence. These preliminary findings lead us to hypothesize that restoring HEV function through LtBR
agonism provides a rational approach towards treated regional recurrence. Aim 1 will focus on the mechanisms
of HEV de-differentiation by Tregs in murine models of regional recurrence. In Aim 2, we will explore the
impact of HEV de-differentiation on cancer cell seeding and quiescence. We expect that this proposal will
provide a mechanistic understanding of how regional recurrence is established and will identify druggable axes
to mitigate this phenomenon.

## Key facts

- **NIH application ID:** 11067411
- **Project number:** 1F31DE034599-01
- **Recipient organization:** UNIVERSITY OF COLORADO DENVER
- **Principal Investigator:** Nicholas A Olimpo
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $43,374
- **Award type:** 1
- **Project period:** 2024-12-01 → 2027-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/11067411

## Citation

> US National Institutes of Health, RePORTER application 11067411, Targeting the Regulation of High Endothelial Venules in HNSCC Regional Recurrence (1F31DE034599-01). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/11067411. Licensed CC0.

---

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