IFNγ-activated dermal lymphatic vessels inhibit cytotoxic T cells in melanoma and inflamed skin
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.
Document Details
- Document Type
- Pub Defense Publication
- Publication Date
- Oct 31, 2018
- Source ID
- 10.1084/jem.20180654
Entities
People
- Alec P. Breazeale
- Amanda W. Lund
- Andy Kaempf
- Christopher P. Loo
- Guillaume Thibault
- Julia Femel
- Motomi Mori
- Ryan S Lane
- Takahiro Tsujikawa
- Young Hwan Chang
Organizations
- Cancer Research Institute
- Kyoto Prefectural University of Medicine
- Melanoma Research Alliance
- National Cancer Institute
- National Institutes of Health
- Oregon Health & Science University
- Swedish Research Council
- United States Department of Defense
- V Foundation for Cancer Research