1. 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
- Author
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Sandrine Prost, Ahsan R. Akram, Helen F Titmarsh, David A. Dorward, Layla Mathieson, Guilia Tagliavini, Kevin Dhaliwal, Richard A. O’Connor, Irene Young, Lilian Koppensteiner, Vishwani Chauhan, and William A Wallace
- Subjects
Interleukin-27 ,Stromal cell ,Lung Neoplasms ,T cell ,T-Lymphocytes ,Immunology ,T cells ,Major histocompatibility complex ,GPI-Linked Proteins ,Ligands ,crosstalk ,Feedback ,Non-small cell lung cancer ,Cancer-Associated Fibroblasts ,Carcinoma, Non-Small-Cell Lung ,medicine ,Tumor Microenvironment ,Immunology and Allergy ,Cytotoxic T cell ,Humans ,Receptor ,5'-Nucleotidase ,RC254-282 ,Original Research ,biology ,Chemistry ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC581-607 ,Immune checkpoint ,medicine.anatomical_structure ,Oncology ,Cancer cell ,Cancer research ,biology.protein ,Immunologic diseases. Allergy ,Research Article - Abstract
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.
- Published
- 2021