Endocrine Abstracts

The immune microenvironment plays a central but ambivalent role in tumourigenesis. During initial phases of neoplasia, both innate and adaptive immune cells recognize and destroy tumour cells. However, during the process of immunoediting, tumour cells progressively reshape the microenvironment and use immune cells to favour neoangiogenesis, tumour growth and metastasis. Until recently, the role of immune response in the pathogenesis of ACC had remained elusive. Analysis of the TCGA gene expression data had suggested that ACC were among the coldest tumours, consistent with the potent immunosuppressive action of glucocorticoids (GCs), produced locally. This was confirmed by immunohistochemical analyses showing that both CD4+ and CD8+ T cells were scarce in ACC. It further showed that tumours with highest levels of GCs were the coldest and the most aggressive. Consistent with low levels of T cells infiltration, clinical trials targeting the PD1/PD-L1 axis failed to significantly increase ACC patients’ overall survival. Interestingly, analysis of a mouse model harbouring deletion of Znrf3 (the most frequent genetic alteration in ACC patients) showed that highly phagocytic MERTK+/TREM2+ macrophages, were efficiently recruited in preneoplastic lesions in male adrenals, preventing formation of aggressive tumours. In contrast, infiltration of MERTK+/ TREM2+ macrophages was lower in female adrenals, allowing for tumour progression and formation of metastatic ACC at 18 months. Analysis of TCGA data further showed that male ACC patients had generally higher levels of phagocytic macrophages signatures, correlated with better prognosis than female patients. Investigation of the mechanisms underlying this sexual dimorphism, showed that testosterone was responsible for the recruitment of phagocytic macrophages, through senescence induction. We are now investigating the downstream targets of androgens to identify factors that could be used to trigger phagocytic macrophage differentiation in ACC patients. This could constitute an exciting alternative therapeutic approach for this cancer, associated with dismal prognosis.