Format

Send to

Choose Destination
J Exp Med. 2018 Oct 31. pii: jem.20180654. doi: 10.1084/jem.20180654. [Epub ahead of print]

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

Author information

1
Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR.
2
Department of Biomedical Engineering and Computational Biology Program, Oregon Health and Science University, Portland, OR.
3
OHSU Center for Spatial Systems Biomedicine, Oregon Health and Science University, Portland, OR.
4
Knight Cancer Institute, Biostatistics Shared Resource, Oregon Health and Science University, Portland, OR.
5
Department of Otolaryngology-Head and Neck Surgery, Kyoto Prefectural University of Medicine, Kyoto City, Kyoto, Japan.
6
Department of Cell, Developmental and Cancer Biology, Oregon Health and Science University, Portland, OR lunda@ohsu.edu.
7
Department of Molecular Microbiology and Immunology, Oregon Health and Science University, Portland, OR.
8
Department of Dermatology, Oregon Health and Science University, Portland, OR.
9
Knight Cancer Institute, Oregon Health and Science University, Portland, OR.

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.

PMID:
30381467
DOI:
10.1084/jem.20180654

Supplemental Content

Full text links

Icon for HighWire
Loading ...
Support Center