Role of AOC1 in modulating the ovarian cancer tumor microenvironment and malignant phenotype

Ovarian cancer can be subdivided into different histologic types. Among them, clear cell ovarian cancer (CCOC), which constitutes 8% of ovarian cancer, differs from the other types with respect to its clinical characteristics. Most of CCOC frequently presents at an early stage compared to high-grade serous ovarian cancer (HGSOC), with most cases diagnosed at Stage I or II, which offers a favorable prognosis. However, those diagnosed with advanced disease experience poorer clinical outcomes compared to those with HGSOC, since CCOC is usually more resistant to systemic chemotherapy than other types. Despite multiple studies showing promise of immune checkpoint inhibitors (ICIs) treatment in patients with CCOC, the molecular mechanisms by which CCOC confers improved response to ICIs, and biomarkers that can predict treatment response to these ICIs in CCOC have not been thoroughly explored. In addition, it remains unclear whether the immune microenvironment plays a role in the early presentation and in metastatic potential of CCOC.Recent spatial transcriptomics (ST) analyses demonstrated that increased AOC1 expression was found in the epithelial cell cluster of early stage CCOC than in HGSOC, which was subsequently validated by sequential immunofluorescence (seqIF) analysis on 17 CCOC and 34 HGSOC patient samples. Increased AOC1 expression is associated with improved overall survival in HGSOC patients. Functional studies showed that despite the lack of a direct effect on the growth of ovarian cancer (OC) cells, syngeneic mouse cells transfected with full-length AOC1 had significantly lower tumor burden than the control mice, suggesting that the tumor microenvironment (TME) mediates the effect of AOC1 on tumor growth. Integrating ST and mass spectrometry imaging (MSI) revealed significantly inverse correlation between AOC1, and histamine and cell membrane VISTA expression levels in cancer cells and/or macrophages in the TME of CCOC and HGSOC, which was confirmed by seqIF. These findings suggest that histamine and VISTA mediate the tumor suppressive effect of AOC1. Indeed, our in vitro studies demonstrated that AOC1 abrogates the growth promoting effect of histamine in OC cells expressing high levels of histamine receptor HRH1, and AOC1 attenuates histamine induced OC proliferation and enhance T cell-mediated anti-tumor immunity via the histamine/HRH1/VISTA axis. Further studies demonstrated that in addition to VISTA, histamine can upregulate PD-L1 in both macrophages and OC cells. AOC1 may increase immune surveillance through attenuating histamine-induced VISTA and PD-L1 expression in the OC TME. Studies to further delineate the immune modulation role of AOC1 and exploring whether enhancing circulating AOC1 levels or targeting histamine with repurposed drugs to improve the efficacy of ICIs as a new strategy in the treatment of OC patients are warranted.