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

Oncoimmunology. 2021 Jul 8;10(1):1940675. doi: 10.1080/2162402X.2021.1940675. eCollection 2021.


The success of immune checkpoint therapy shows tumor-reactive T cells can eliminate cancer cells but are restrained by immunosuppression within the tumor micro-environment (TME). Cancer associated fibroblasts (CAFs) are the dominant stromal cell in the TME and co-localize with T cells in non-small cell lung cancer. We demonstrate the bidirectional 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 bidirectional 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.

Keywords: Non-small cell lung cancer; T cells; cancer-associated fibroblasts; crosstalk.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 5'-Nucleotidase*
  • Cancer-Associated Fibroblasts*
  • Carcinoma, Non-Small-Cell Lung* / genetics
  • Feedback
  • GPI-Linked Proteins
  • Humans
  • Interleukin-27*
  • Ligands
  • Lung Neoplasms* / genetics
  • T-Lymphocytes*
  • Tumor Microenvironment / genetics


  • GPI-Linked Proteins
  • Interleukin-27
  • Ligands
  • 5'-Nucleotidase
  • NT5E protein, human

Grant support

This work was supported by the Cancer Research UK [CRUK Clinician Scientist Fellowship A24867]; EPSRC Centre for Doctoral Training in Medical Imaging [EP/L016559/1].