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Cancer-associated fibroblasts induce antigen-specific deletion of CD8 + T Cells to protect tumour cells.

Published version
Peer-reviewed

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Authors

Lakins, Matthew A 
Ghorani, Ehsan 
Munir, Hafsa 
Martins, Carla P 
Shields, Jacqueline D 

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 neutralisation 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.

Description

Keywords

Animals, Antigens, Neoplasm, CD8-Positive T-Lymphocytes, Cancer-Associated Fibroblasts, Cell Survival, Cross-Priming, Cytoprotection, Cytotoxicity, Immunologic, Fas Ligand Protein, Female, Mice, Inbred C57BL, Programmed Cell Death 1 Ligand 2 Protein, Proteolysis

Journal Title

Nat Commun

Conference Name

Journal ISSN

2041-1723
2041-1723

Volume Title

9

Publisher

Springer Science and Business Media LLC
Sponsorship
Medical Research Council (MC_UU_12022/4)
MRC (unknown)
Medical Research Council (MC_UU_12022/5)
Worldwide Cancer Research (formerly AICR) (12-0115)