PTEN loss shapes macrophage dynamics in ovarian high grade serous carcinoma
Ovarian high grade serous carcinoma (HGSC) remains a disease of poor prognosis that is unresponsive to current immune checkpoint inhibitors. Although PI3K pathway alterations are common in HGSC, attempts to target this pathway have been unsuccessful. We hypothesised that aberrant PI3K pathway activation may alter the HGSC immune microenvironment and present a novel targeting strategy. We used murine models and HGSC patient samples to study the impact of loss of Pten, a negative regulator of PI3K pathway signalling. We identified populations of resident macrophages specifically in Pten null omental tumours. These macrophages derive from peritoneal fluid macrophages and have a unique gene expression programme, marked by high expression of the enzyme heme oxygenase-1 (HMOX1). We show that Pten null cells produce known activators of HMOX1hi macrophage gene programme and that targeting resident peritoneal macrophages prevents appearance of HMOX1hi macrophages and reduces tumour growth. Furthermore, direct inhibition of HMOX1 extends survival in vivo. HMOX1hi macrophages with corresponding gene expression programmes are identified in human HGSC tumours and their presence correlates with activated tumoural PI3K pathway/mTOR signalling and poor overall survival in HGSC patients. In contrast, tumours with a low number of HMOX1hi macrophages are marked by increased adaptive immune response gene expression. Our data suggest that HMOX1hi macrophages represent a potential therapeutic target and biomarker for poor prognosis HGSC.