V gamma 1 gamma-delta T cells steer airway macrophages towards a pro-fibrotic response in an autochthonous lung cancer mouse model. [RNA-Seq]

Gamma-delta T cells are important for host defence at the respiratory mucosa, acting directly or through interactions with other cells. However, how Gamma-Delta T cells influence other immune cells in the lung remains unclear. Using a genetically engineered mouse model of lung cancer, we show that tumours drive expansion of both CD27+ and CD27— Gamma-Delta T cells. Advanced microscopy techniques indicated that CD27— Gamma-Delta T cells are enriched in tumours, while CD27+ Gamma-Delta T cells are more prone to interact with macrophages in tumour-associated adventitial cuffs. SiglecFlow pro-fibrotic airway macrophages were more prevalent in lung tumour-bearing mice than tumour-free mice. This pro-fibrotic subset was reduced in lungs when the cancer model was crossed to Tcrd knockout mice or treated with V Gamma1-depleting antibodies, but not in TcrgV4/6 knockout mice. Thus, our findings implicate V Gamma1 Gamma-Delta T cells in driving tumour-associated airway macrophage functional imprinting. Determining the translatability to human health may offer new avenues for refining patient management and immunotherapeutic strategies. Overall design: Bulk RNA-seq was performed on FACS-isolated alveolar macrophage subsets from: 1) Tumour-bearing KM lungs from Tcrd knockout mice vs wild type to identify differentially expressed genes. These genes were used to create a module score for assessing scRNA-seq clusters. 2) Tumour-bearing KM lungs, comparing SiglecF low and SiglecF hi AMs to define transcriptional programmes associated with profibrotic versus immunoreactive states; these signatures were then related back to scRNA-seq clusters.