Impact of Tumor-Associated Lymphangiogenesis on Heterologous Prime-Boost Vaccine Efficacy

Diplôme Thèse Impact of Tumor-Associated Lymphangiogenesis on Heterologous Prime-Boost Vaccine Efficacy eng 2026-06-25 2026-06-25 author Yeturu Lakshmi 986355 director Hugues Stéphanie 663452 Département de pathologie et immunologie (PATIM) director Santiago-Raber Marie-Laure 556511 Département de pathologie et immunologie (PATIM) 231 10.13097/archive-ouverte/unige:195348 urn:nbn:ch:unige-1953484 Sc. Vie - Bioméd. 401 <p>The lymphatic vasculature is the second largest component of the circulatory system and consists of a hierarchical network of lymphatic vessels (LVs) that is important for the passive transport of fluids, immune cells, and macromolecules. Recent evidence highlights the important immunomodulatory role of lymphatic endothelial cells (LECs) lining LVs, which regulate immune cell traCicking, antigen cross-presentation, and peripheral tolerance. Although tumor-associated LVs are traditionally associated with poor prognosis and overall survival in many cancers, recent evidence in melanoma has uncovered a more immunostimulatory role for LECs. In this tumor-context, LVs promote immune cell infiltration and enhance therapeutic eCicacy of immune checkpoint blockade (ICB).</p> <p>We have previously shown that a heterologous prime boost vaccination strategy of KISIMA/VSV-GP with matching tumor associated antigens (TAAs), combined with ICB, anti-PD-1 (αPD-1) therapy, demonstrated preclinical eCicacy in non-lymphangiogenic tumor models. However, these eCects were not durable in murine melanoma-bearing mice and the tumor intrinsic factors determining response to this treatment remain incompletely understood. Here we show that both the therapeutic eCicacy and dependency on the combination with αPD-1 is shaped by the lymphatic architecture of the tumor microenvironment. Using murine melanoma models, with two distinct lymphatic landscapes, we demonstrate that combining the chimeric peptide vaccine, KISIMA with recombinant VSV-GP-TAA viral vector in a heterologous prime-boost regimen, induces robust tumor control in lymphangiogenic B16ovaVC tumors without the need for ICB. Elevated lymphatic density was associated with an increased CD45+ immune infiltration and a sustained recruitment of naive like T lymphocytes, supporting intratumoral priming and diCerentiation into eCector or memory T cells. In addition, vaccination also induces a pro-inflammatory program in tumoral LECs. In contrast, in poorly lymphangiogenic B16ovaWT tumors, limited LVs restricted immune influx into the TME, vaccination promotes T cell exhaustion, rendering its eCicacy dependent on checkpoint blockade-mediated T cell reinvigoration. Collectively, these findings highlight the active role of tumor-associated LECs in shaping the eCicacy to combination therapies.</p> Lymphatic Immunology Cancer Vaccination Melanoma Dewey 616.07 137 Département de pathologie et immunologie 21F false a0be35fd-b066-480a-bae1-f5c47a9e3077 Thesis Restricted YETURU_Thesis_Manuscript_2026.pdf 30834719 application/pdf cb5299b520bacdb3042aa4406ed82270eec67a8a06b3484c777f3df3b5d9b540 f6b62240-28b9-4a21-add6-d69f5cfa2a76 Imprimatur Public file.pdf 184597 application/pdf b81eb8fdb7ad74d1a6f56d8d360d5a4c9fdc14a72200d5667e11e94afb39f504 restrictedAccess Faculté de médecine / Section de médecine fondamentale / Département de pathologie et immunologie

Title	Published in	Access level	OA Policy	Year	Views	Downloads

Impact of Tumor-Associated Lymphangiogenesis on Heterologous Prime-Boost Vaccine Efficacy				2026	13	2

Archive ouverte UNIGE

Yeturu, Lakshmi

account_balance UNIGE affiliation entities

UNIGE research groups

UNIGE affiliation entities