T cells drive negative feedback mechanisms in cancer associated fibroblasts, promoting expression of co-inhibitory ligands, CD73 and IL-27 in non-small cell lung cancer

The success of immune checkpoint therapy shows tumour-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumour micro-environment (TME). Cancer Associated Fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localise with T cells in non-small cell lung cancer. We demonstrate the bi-directional nature of CAF / T cell interactions; T cells promote expression of co-inhibitory ligands, MHC molecules and CD73 on CAFs, increasing their production of IL-6 and eliciting production of IL-27. In turn CAFs upregulate co-inhibitory receptors on T cells including the ectonucleotidase CD39 promoting development of an exhausted but highly cytotoxic phenotype. Our results highlight the bi-directional interaction between T cells and CAFs in promoting components of the immunosuppressive CD39, CD73 adenosine pathway and demonstrate IL-27 production can be induced in CAF by activated T cells.