Lymphangiogenesis driven by VEGF-C reshapes tumor immune landscape and enables tumor eradication by viral immunotherapy in mouse melanoma models.

Vascular Endothelial Growth Factor C (VEGF-C), a key lymphangiogenic growth factor, has been implicated in improving responses to cancer immunotherapy. We investigated the impact of VEGF-C on the efficacy of oncolytic virotherapy with avian paramyxoviruses APMV-1 (NDV) and APMV-4. Treatment of B16F10 tumors lacking VEGF-C delays tumor growth, and complete responses (CRs) are rare. In contrast, virotherapy of VEGF-C-expressing tumors leads to CRs in most mice. Rechallenged mice remain tumor- and metastasis-free for over two years, indicating durable immunity. VEGF-C-induced lymphangiogenesis correlates with high CD8+ and CD4+ T cell densities near lymphatic vessels. Spectral flow cytometry shows changes in the composition and activation of CD8+ T cells, CD4+ T cells and NK cells associated with CRs, including enrichment of CD8+CD25+PD-1+ effector T cells. T cell composition changes in sentinel and contralateral lymph nodes, indicating a systemic response. These findings demonstrate that VEGF-C-driven remodeling of the tumor immune microenvironment enables durable CRs to APMV virotherapy.