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

• Published in: Nature communications Vol. 9; no. 1; pp. 948 - 9
• Main Authors: Lakins, Matthew A., Ghorani, Ehsan, Munir, Hafsa, Martins, Carla P., Shields, Jacqueline D.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05-03-2018; Nature Publishing Group; Nature Portfolio
• Subjects: 13/106; 13/109; 14/1; 14/34; 14/35; 14/63; 631/250/21; 631/67/327; 631/67/580/1884; 64/60; 82/51; 96; 96/31; Animals; Antigens; Antigens, Neoplasm - immunology; Cancer; Cancer-Associated Fibroblasts - pathology; CD8 antigen; CD8-Positive T-Lymphocytes - immunology; Cell Survival; Clonal deletion; Cross-Priming - immunology; Crosstalk; Cytoprotection; Cytotoxicity; Cytotoxicity, Immunologic; Fas Ligand Protein - metabolism; FasL protein; Female; Fibroblasts; Humanities and Social Sciences; Immune checkpoint; Immune response; Lymphocytes; Lymphocytes T; Mice, Inbred C57BL; multidisciplinary; Programmed Cell Death 1 Ligand 2 Protein - metabolism; Proteolysis; Science; Science (multidisciplinary); Stromal cells; Tumor microenvironment; Tumors
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/s41467-018-03347-0

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.
Tumours employ a variety of strategies to induce immune suppression. Here the authors show that cancer-associated fibroblasts process and cross-present tumour-antigens to T-cells resulting in antigen-specific T cell death and dysfunction via upregulation of both cell death and immune checkpoint signals.