Targeting the Regulation of High Endothelial Venules in HNSCC Regional Recurrence - 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.
