Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.
Authors
Lakins, Matthew A
Ghorani, Ehsan
Munir, Hafsa
Pedro Martins, Carla
Shields, Jacqueline
Publication Date
2018-03-05Journal Title
Nature communications
ISSN
2041-1723
Publisher
Springer Nature
Volume
9
Issue
1
Pages
948
Language
eng
Type
Article
This Version
VoR
Physical Medium
Electronic
Metadata
Show full item recordCitation
Lakins, M. A., Ghorani, E., Munir, H., Pedro Martins, C., & Shields, J. (2018). Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.. Nature communications, 9 (1), 948. https://doi.org/10.1038/s41467-018-03347-0
Abstract
Tumours have developed strategies to interfere with most steps required for anti-tumour immune responses. Although many populations contribute to anti-tumour responses, tumour-infiltrating cytotoxic T cells dominate, hence many suppressive strategies act to inhibit these. Tumour-associated T cells are frequently restricted to stromal zones rather than tumour islands, raising the possibility that the tumour microenvironment, where crosstalk between malignant and “normal” stromal cells exists, may be critical for T cell suppression. We provide evidence of direct interactions between stroma and T cells driving suppression, showing that cancer-associated fibroblasts (CAFs) sample, process and cross-present antigen, killing CD8+ T cells in an antigen-specific, antigen-dependent manner via PD-L2 and FASL. Inhibitory ligand expression is observed in CAFs from human tumours, and neutralization of PD-L2 or FASL reactivates T cell cytotoxic capacity in vitro and in vivo. Thus, CAFs support T cell suppression within the tumour microenvironment by a mechanism dependent on immune checkpoint activation.
Keywords
CD8-Positive T-Lymphocytes, Animals, Mice, Inbred C57BL, Antigens, Neoplasm, Cell Survival, Cross-Priming, Cytotoxicity, Immunologic, Cytoprotection, Female, Fas Ligand Protein, Programmed Cell Death 1 Ligand 2 Protein, Proteolysis, Cancer-Associated Fibroblasts
Sponsorship
Medical Research Council (MC_UU_12022/4)
MRC (MC_UU_12022/1_do not transfer?)
Medical Research Council (MC_UU_12022/5)
Worldwide Cancer Research (formerly AICR) (12-0115)
Embargo Lift Date
2100-01-01
Identifiers
External DOI: https://doi.org/10.1038/s41467-018-03347-0
This record's URL: https://www.repository.cam.ac.uk/handle/1810/275521
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