The contribution of lymphatic and blood endothelial cell PD-L1 to leukocyte accumulation in skin Public Deposited

Mechanisms of immune suppression in peripheral tissues counteract protective immu-nity to prevent immunopathology and are coopted by tumors for immune evasion. Blood and lymphatic vessels contribute to the immune landscape within a tissue by providing selective entry and exit routes, respectively. The work here investigates potential mecha-nisms by which peripheral lymphatic and blood vessel expression of the T cell inhibitory molecule PD-L1, regulate antitumor immunity. Here I test the hypothesis that PD-L1 expression by blood and lymphatic vasculature limits T cell accumulation in skin and tu-mors. Initial studies demonstrated that both lymphatic and blood endothelial cells (LECs and BECs, respectively) express PD-L1 in the tumor microenvironment and loss of non-hematopoietic PD-L1 results in increased T cell accumulation in tumors. I show that LECs express PD-L1 following cutaneous viral infection in response to IFNγ produced by infiltrating CD8+ T cells and prevent immunopathology by limiting T cell accumula-tion. Additionally, this feedback mechanism limiting T cell accumulation by lymphatic vessels is coopted by melanoma tumors. The inability for LECs to respond to IFNγ in-creases T cell-dependent tumor control and extends survival in mice. Therefore I identify tumor associated lymphatic vessels as a component of adaptive immune resistance in tu-mors that likely contributes to patient response to immune checkpoint blockade. Though BECs express PD-L1 at sites of ongoing inflammation, I show that BECs also express PD-L1 constitutively at steady state in the skin of mice. Here I test the hypothesis that PD-L1 expression by BECs inhibits leukocyte transmigration across poorly or uninflamed endothelial barriers. I demonstrate that this BEC PD-L1 expression is actively maintained by STAT1 signals and marks a subset of capillary endothelial cells. Interestingly, I demon-strate that blockade of PD-L1, but not PD-1, following viral infection increases monocyte accumulation in uninfected skin, indicating that BEC PD-L1 may inhibit monocyte ac-cumulation independent of PD-1. Moving forward I will test the hypothesis that PD-L1 signals internally within cutaneous BECs and stabilizes endothelial cell-cell junctions.

  • lane.ryan.2019.pdf
Publication Date
  • 2019
Document type