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bioRxiv · 10.1101/2025.08.27.672466

Lymphangiogenesis driven by VEGF-C reshapes tumor immune landscape and enables tumor eradication by viral immunotherapy

Fernandez-Rodriguez, R.·Castano, S. C.·Edwards, A. K.·Rogic, A.·Bykov, Y.·Mena, I.·Freire, N. D.·Kamphorst, A. O.·Karlic, R.·Horowitz, A.·Garcia-Sastre, A.·Skobe, M.
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Abstract

Vascular Endothelial Growth Factor C (VEGF-C) is a key lymphangiogenic growth factor expressed by many types of cancer. Here, we investigated the effects of tumor-derived VEGF-C on the therapeutic efficacy of oncolytic virotherapy with avian paramyxoviruses APMV-1 (NDV) and AMPV-4. Treatment of B16F10 tumors not expressing VEGF-C with either virus led to tumor growth delay, and complete responses were rare. In contrast, when tumors expressed VEGF-C, viral therapy led to complete remission and long-term immunological memory in most mice. Upon re-challenge, most mice remained tumor- and metastasis-free for over 18 months, indicating durable immunity. VEGF-C induced tumor lymphangiogenesis, which correlated with high CD8+ and CD4+ T-cell densities in proximity of lymphatic vessels. Spectral flow cytometry revealed distinct changes in the composition and activation of CD8+, CD4+ T cells and NK cells associated with complete remission. In responders, tumors were highly enriched in CD8+CD25+ PD-1+ effector T cells. Composition of T cells was altered in sentinel and in contralateral lymph nodes, indicating a systemic immune response. Taken together, these data demonstrate VEGF-C-induced changes in tumor immune landscape which are critical for achieving complete response and support combining VEGF-C with APMV virotherapy as a novel highly effective strategy for cancer treatment.

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Fernandez-Rodriguez, R., Castano, S. C., Edwards, A. K., Rogic, A., Bykov, Y., Mena, I., Freire, N. D., Kamphorst, A. O., Karlic, R., Horowitz, A., Garcia-Sastre, A., Skobe, M.. 2025-09-01. Lymphangiogenesis driven by VEGF-C reshapes tumor immune landscape and enables tumor eradication by viral immunotherapy. https://doi.org/10.1101/2025.08.27.672466

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