IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin

Ryan S. Lane, Julia Femel, Alec P. Breazeale, Christopher P. Loo, Guillaume Thibault, Andy Kaempf, Motomi (Tomi) Mori, Takahiro Tsujikawa, Young Hwan Chang, Amanda Lund

Research output: Contribution to journalArticle

17 Scopus citations

Abstract

Mechanisms of immune suppression in peripheral tissues counteract protective immunity to prevent immunopathology and are coopted by tumors for immune evasion. While lymphatic vessels facilitate T cell priming, they also exert immune suppressive effects in lymph nodes at steady-state. Therefore, we hypothesized that peripheral lymphatic vessels acquire suppressive mechanisms to limit local effector CD8+ T cell accumulation in murine skin. We demonstrate that nonhematopoietic PD-L1 is largely expressed by lymphatic and blood endothelial cells and limits CD8+ T cell accumulation in tumor microenvironments. 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. Disruption 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. Consequently, we identify IFNγR as an immunological switch in lymphatic vessels that balances protective immunity and immunopathology leading to adaptive immune resistance in melanoma.

Original languageEnglish (US)
Pages (from-to)3057-3074
Number of pages18
JournalJournal of Experimental Medicine
Volume215
Issue number12
DOIs
Publication statusPublished - Dec 1 2018

    Fingerprint

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this