Single-cell sequencing of PIT1-positive pituitary adenoma highlights the pro-tumour microenvironment mediated by IFN-γ-induced tumour-associated fibroblasts remodelling

Background PIT1-positive pituitary adenoma (PIT1-PA) is one of the most important lineages of pituitary adenoma (PA), which causes systematic endocrine disorders and a worse prognosis. Tumour-associated fibroblast (TAF) is a crucial stroma cell type in the tumour microenvironment (TME). However, cellular and functional heterogeneity of TAF and immune cells in PIT1-PA have not been fully investigated. Methods By single-cell RNA sequencing of four PIT1-PAs and further analyses, we characterised the molecular and functional profiles of 28 different cell subtypes. Results PA stem cells in PIT1/SF1-positve PA were in a hybrid epithelial/mesenchymal state, and differentiated along the PIT1- and SF- dependent branches. C1Q was overwhelmingly expressed in tumour-associated macrophages, indicating its pro-tumoral functionality. PIT1-PA progression was characterised by lower cell–cell communication strength and higher cell adhesion-associated signals, indicating the immunosuppressive but pro-invasive microenvironment. IFN-γ signal repressed functional remodelling of myofibroblastic TAF (mTAF) towards inflammatory TAF/antigen-presenting TAF. IFN-γ inhibited mTAF phenotypes and N-cadherin expression through STAT3 signal axis. CDH2 knockdown in TAFs abrogated their pro-tumour function in PAs. Conclusions Our study builds up a cellular landscape of PIT1-PA TME and highlights anti-tumour function of IFN-γ mediated TAF remodelling, which benefits clinical treatments and drug development.