Peripheral tissues adopt mechanisms of immune suppression that counteract protective immunity to prevent immunopathology and are co-opted by tumors for immune escape. In tumors, cytotoxic, antigen-specific T cells produce IFNg and activate multiple mechanisms of adaptive immune resistance, including upregulation of the T-cell inhibitory molecule programed death ligand 1 (PD-L1). Tumor cell PD-L1 expression does not predict response to anti-PD-L1 immunotherapy, indicating, however, that other sources of PD-L1 in tumor microenvironments may contribute to PD-L1-dependent immune suppression. Lymphatic vessels facilitate antigen and dendritic cell transport to draining lymph nodes and are required for antitumor immunity. Interestingly, lymphatic endothelial cells in lymph nodes are tolerogenic at steady-state and constitutively express PD-L1 to delete self-reactive CD8+ T cells. However, whether lymphatic endothelial cells in tumor microenvironments are also directly immunosuppressive remains unclear. Here we test the hypothesis that peripheral, tumor-associated lymphatic vessels acquire immunosuppressive mechanisms, e.g., PD-L1 expression, that limit effector CD8+ T-cell accumulation and function in melanoma. We demonstrate that host nonhematopoietic, nontumor, PD-L1 limits CD8+ T-cell accumulation in murine melanoma. Further, we show that tumor-associated lymphatic endothelial cells upregulate PD-L1 in response to IFNg produced by tumor-infiltrating, antigen-specific CD8+ T cells. As such, loss of IFNgR by lymphatic endothelial cells improves CD8+ T-cell accumulation in murine melanomas, thereby enhancing tumor control and improved overall survival. Importantly, this robust lymphatic vessel-dependent tumor control was revealed in the context of murine melanomas with significant UVB-induced somatic mutation burden, consistent with a cytotoxic T cell-mediated negative feedback mechanism. Consequently, we present IFNg-mediated activation of tumor-associated lymphatic vessels as a new component of adaptive immune resistance, suggesting that context-dependent lymphatic vessel function may provide novel, targetable mechanisms of immune control in melanoma.

Citation Format: Ryan S. Lane, Alec P. Breazeale, Amanda W. Lund. IFNg-activated lymphatic vessels express PD-L1 and suppress effector T-cell function in melanoma [abstract]. In: Proceedings of the AACR Special Conference on Tumor Immunology and Immunotherapy; 2018 Nov 27-30; Miami Beach, FL. Philadelphia (PA): AACR; Cancer Immunol Res 2020;8(4 Suppl):Abstract nr A78.