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

10 Citations (Scopus)

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
StatePublished - Dec 1 2018

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Lymphatic Vessels
Melanoma
T-Lymphocytes
Skin
Immunity
Lymphatic Vessel Tumors
Tumor Escape
CD8 Antigens
Tumor Microenvironment
Blood Cells
Endothelial Cells
Lymph Nodes
Pathology
Neoplasms

ASJC Scopus subject areas

  • Immunology and Allergy
  • Immunology

Cite this

IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin. / Lane, Ryan S.; Femel, Julia; Breazeale, Alec P.; Loo, Christopher P.; Thibault, Guillaume; Kaempf, Andy; Mori, Motomi (Tomi); Tsujikawa, Takahiro; Chang, Young Hwan; Lund, Amanda.

In: Journal of Experimental Medicine, Vol. 215, No. 12, 01.12.2018, p. 3057-3074.

Research output: Contribution to journalArticle

Lane, Ryan S. ; Femel, Julia ; Breazeale, Alec P. ; Loo, Christopher P. ; Thibault, Guillaume ; Kaempf, Andy ; Mori, Motomi (Tomi) ; Tsujikawa, Takahiro ; Chang, Young Hwan ; Lund, Amanda. / IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin. In: Journal of Experimental Medicine. 2018 ; Vol. 215, No. 12. pp. 3057-3074.
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AU - Loo, Christopher P.

AU - Thibault, Guillaume

AU - Kaempf, Andy

AU - Mori, Motomi (Tomi)

AU - Tsujikawa, Takahiro

AU - Chang, Young Hwan

AU - Lund, Amanda

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