Lakins et al. demonstrated that cancer-associated fibroblasts (CAFs) protect tumor cells by processing and cross-presenting antigens on MHC I molecules, upregulating FASL/PD-L2, and driving upregulation of FAS/PD-1 on T cells, leading to the death and exhaustion of antigen-specific CD8+ T cells. Neutralizing antibodies against FASL or PD-L2 increased the infiltration of CD8+ T cells into the tumor and led to tumor reduction. RNA expression and immunofluorescence confirmed increased PD-L2 in CAFs in various human tumor types.

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.

Author Info: (1) Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. (2) Medical Research Council Cancer Unit, University of Cambridge

Author Info: (1) Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. (2) Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. (3) Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. (4) Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. (5) Medical Research Council Cancer Unit, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0XZ, UK. js970@mrc-cu.cam.ac.uk.

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