IFNg-activated dermal lymphatic vessels restrict anti-tumor immunity

Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune escape. While lymphatic vessels facilitate T cell priming through dendritic cell and antigen delivery to lymph nodes, they also exert PD-L1-dependent immune suppressive effects in lymph nodes at steady state, and facilitate melanoma metastasis. How lymphatic vessels may switch between immunogenic and immune suppressive roles remains and area of active investigation. Here we demonstrate a specific role for non-hematopoietic, non-tumor PD-L1, in limiting CD8+ T cell accumulation in melanoma. We find that IFNg produced by tissue infiltrating, antigen-specific CD8+ T cells is sufficient to activate lymphatic vessel PD-L1 expression. As such, disruption of IFNg-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in melanoma leading to CD8+ T cell-mediated tumor control and improved overall survival. Importantly, robust lymphatic vessel-dependent tumor control was revealed in the context of murine melanomas with significant UVB-induced somatic mutation burden, consistent with our model of cytotoxic T cell-activated mechanisms of negative feedback. Consequently, we present IFNg-mediated activation of tumor-associated lymphatic vessels as an important immunological switch in skin and tumors that contributes to adaptive immune resistance. We suggest that a continued understanding of context-dependent lymphatic vessel function will to reveal novel mechanisms of immune control and metastasis in melanoma.

Learning Objectives:

1. Define the impact of PD-L1 expressed on non-tumor, non-hematopoietic cells in T cell-mediated tumor control

2. Reveal the contribution of IFNg signaling in dermal lymphatic vessels to tumor control

3. Explain the contribution of adaptive immune resistance to immunotherapy response