Aggressive pituitary neuroendocrine tumours display a distinct immune microenvironment

BACKGROUND AND AIMS: There is an ongoing need to identify prognostic and therapeutic biomarkers and develop alternative treatment options to treat aggressive and metastatic pituitary neuroendocrine tumours (PitNETs). This study aimed to examine the pituitary tumour immune microenvironment and correlate this with tumour behaviour to identify novel biomarkers. METHODS: This was a retrospective study of patients who underwent surgical resection of aggressive and non-aggressive PitNETs. Immune cells, immune checkpoints, and markers of cell cycle regulation and senescence were analysed using immunohistochemistry. Cytokines and chemokines were analysed using a multiplex immunoassay. RESULTS: Forty-eight PitNET samples were included in the study. 12 were classified as aggressive PitNETs (APT) and 3 died from pituitary disease. APTs compared with non-APTs had higher CD3 T lymphocyte and CD163 macrophage infiltrate as well as lower expression of IFN-γ and PDGFAA. On analysis of tumour types this was also observed in aggressive Pit1 PitNETs compared with SF1 PitNETs. Compared with SF1 PitNETs both aggressive and non-aggressive Pit1 PitNETs exhibited increased expression of checkpoint marker PDL1 and senescence markers p16 and p21. Pit1 and TPit PitNETs were more likely to demonstrate a perivascular pattern of immune cell infiltrate than SF1 PitNETs. MIG, MIP1β and IL1RA positively correlated with T lymphocytes, dendritic cells, and CD163 macrophages. Increased CD163 was associated with tumour recurrence, and increased IL8 and TGFβ was associated with death from pituitary disease. CONCLUSIONS: Aggressive PitNETs display a distinct tumour microenvironment characterised by increased immune cell infiltrate. These findings may offer novel prognostic biomarkers and therapeutic targets.