![]() ![]() Thus, lymphatic transport shapes inflammatory and immune microenvironments in solid tumors ( Lund, 2016). Consistent with the role for lymphatic vessels in de novo adaptive immunity, lymphatic vessel density (LVD) in primary tumors of colorectal patients positively correlates with intratumoral CD8 + T cell infiltrates ( Mlecnik et al., 2016 Bordry et al., 2018), and similarly, work in mouse models demonstrates a causal relationship between tumor-associated lymphangiogenesis and intratumoral inflammation ( Lund et al., 2012, 2016b Alitalo et al., 2013 Fankhauser et al., 2017) leading to improved response to immunotherapy ( Fankhauser et al., 2017). Lymphatic vessels transport antigen and dendritic cells (DCs) to LNs to prime naive T cells following peripheral tissue viral infection ( Allan et al., 2006 Bedoui et al., 2009 Loo et al., 2017) and remain the main route of DC migration and de novo immune priming in tumors ( Lund et al., 2016b Roberts et al., 2016). Lymphatic vessels compose a hierarchical vasculature that facilitates the unidirectional transport of fluid and cells from peripheral, blind-ended capillaries through collecting vessels to lymphatic sinuses in secondary lymphoid organs ( Stacker et al., 2014). Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma. PROTA STRUCTURE 2018 ACTIVATION SKINDisruption of IFNγ-dependent crosstalk through lymphatic-specific loss of IFNγR boosts T cell accumulation in infected and malignant skin leading to increased viral pathology and tumor control, respectively. IFNγ produced by tissue-infiltrating, antigen-specific CD8 + T cells, which are in close proximity to tumor-associated lymphatic vessels, is sufficient to induce lymphatic vessel PD-L1 expression. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8 + T cell accumulation in tumor microenvironments. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8 + T cell accumulation in murine skin. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. ![]() ![]() Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. ![]()
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