Abstract LB075: VEGF-C remodels the tumor microenvironment during immunotherapy response in melanoma and promotes T cell memory

Abstract Tumor-associated lymphatic vessels are clinically linked to aggressive tumor progression and metastasis. Their expansion is driven by vascular endothelial growth factor-C (VEGF-C), which is highly expressed in the tumor microenvironment (TME) in melanoma and other solid tumors. Although elevated VEGF-C promotes an immunosuppressive TME, it paradoxically also enhances the response to immunotherapy in mouse models and correlates with improved survival after checkpoint blockade in patients. This enhanced response was associated with VEGF-C-induced alterations in the tumor microenvironment before immunotherapy, characterized by increased infiltration of naïve T cells in VEGF-C-overexpressing tumors, which creates favorable conditions for local T cell activation. Here, we investigated how VEGF-C reshapes the tumor microenvironment during and after immunotherapy response to improve immunotherapy outcome in melanoma, focusing on immune cell trafficking and memory T cell development. We utilized a B16F10 melanoma model overexpressing VEGF-C (B16-VEGFC) or a control vector (B16-Control) in conjunction with the pmel adoptive cell transfer and peptide vaccination model. Our data demonstrate that B16-VEGFC tumors harbor increased transferred antigen-specific T cells, including more proliferating effector and central memory T cells, along with enhanced endogenous T and B cell populations. In parallel, B16-VEGFC tumors and their draining lymph nodes (tdLN) contain higher fractions of total memory T cells, and Tcf1+ stem-like memory T cells in lymphangiogenic tumors localize near lymphatic vessels. In addition to T cell memory, B16-VEGFC tumors and tdLN exhibit enhanced CD103+ dendritic cell trafficking. Moreover, bystander activation and proliferation of non-targeted CD8 T cells increase in B16-VEGFC tumors, indicating robust immune activation through antigen spreading. Collectively, our study establishes that VEGF-C is pivotal in shaping the anti-tumor immune response during immunotherapy by altering both the TME and the systemic immune response. By promoting T cell memory, boosting DC trafficking, and facilitating T cell recruitment, VEGF-C drives a more robust and sustained immune response against melanoma. Future research using photoconvertible mice will further elucidate the trafficking dynamics between the tumor and its draining lymph nodes post-immunotherapy, providing a more comprehensive understanding of VEGF-C's impact on the tumor microenvironment before and during immunotherapy. Citation Format: Colleen Foley, Lambert Potin, Casey Propst, Melody A. Swartz. VEGF-C remodels the tumor microenvironment during immunotherapy response in melanoma and promotes T cell memory [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB075.