Centre for Inflammation Research, Queen's Medical Research Institute, University of Edinburgh, Edinburgh, UK.
Edinburgh Medical School, The Chancellor's Building, University of Edinburgh, Edinburgh, UK.
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.
免疫检查点治疗的成功表明，肿瘤反应性 T 细胞可以消除癌细胞，但在肿瘤微环境（TME）中受到免疫抑制的限制。癌症相关成纤维细胞（CAF）是 TME 中占主导地位的基质细胞，与非小细胞肺癌中的 T 细胞在局部共存。我们证明了 CAF/T 细胞相互作用的双向性；T 细胞促进 CAF 上共抑制配体、MHC 分子和 CD73 的表达，增加其 IL-6 的产生，并引发 IL-27 的产生。反过来，CAF 上调 T 细胞上的共抑制受体，包括外核苷酸酶 CD39，促进衰竭但高度细胞毒性表型的发展。我们的结果强调了 T 细胞和 CAF 之间促进免疫抑制性 CD39、CD73 腺苷途径成分的双向相互作用，并证明激活的 T 细胞可以诱导 CAF 中产生 IL-27。
