Immune Landscape of Pituitary Neuroendocrine Tumours Reveals Association between Macrophages and Gonadotroph-Tumour Invasion.

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Pituitary neuroendocrine tumours (PitNETs) are frequent intracranial neoplasms that present heterogenic characteristics. Little is known about the immune cell network that exists in PitNETs and its contribution to their aggressive behaviour.Here we combined flow cytometry, t-SNE analysis and histological approaches to define the immune landscape of surgically resected-PitNETs. Xenografts of rodent pituitary tumour-cells and resected PitNETs were performed in Rag2KO mice, in combination with in vitro analysis aimed at dissecting the role of pituitary tumour-cells in monocyte recruitment.We report that gonadotroph-PitNETs present an increased CD68+ macrophage signature compared to somatotroph-, lactotroph- and corticotroph-PitNETs. Transcriptomic and histological characterisations confirmed gonadotroph infiltrating macrophages expressed CD163, MRC-1, ARG1 and CSF1R M2-macrophage markers. Use of GH3/GH4 somatotroph- and LβT2/αT3.1 gonadotroph-cells drove THP1 macrophage migration through respective expression of CCL5 or CSF1. Although both LβT2 and GH3 cells recruited F4/80 macrophages following their engraftment in mice, only LβT2-gonadotroph cells showed a capacity for M2-like polarisation. Similar observations were performed on patient-derived xenografts from somatotroph- and gonadotroph-tumours. Analysis of clinical data further demonstrated a significant correlation between the percentage of CD68+ and CD163+ infiltrating macrophages and the invasive character of gonadotroph-tumours.Gonadotroph-tumours drive the recruitment of macrophages and their subsequent polarisation to an M2-like phenotype. More importantly, the association between infiltrating CD68+/CD163+ macrophages and invasiveness of gonadotroph-tumours points to macrophage-targeted immunotherapies being a potent strategy to limit the progression of gonadotroph-PitNETs.

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