Cheng Wang

Hypoxia induced VEGF secretion promotes resistance to bispecific T-cell engagers

Abstract Bispecific T-cell Engagers (BITEs) are a novel form of immunotherapy that overcome a deficiency of immune checkpoint inhibitors (ICI) by targeting a preidentified tumor associated antigen and redirecting a polyclonal population of effector T-cells against the tumor. High grade serous ovarian cancer is a lethal disease in the recurrent setting and has not been amenable to ICI therapy. MUC16/CA125 is overexpressed in high grade serous ovarian cancer. BITEs targeting the tumor-retained portion of MUC16/CA125 have recently been described and are in early-phase clinical trials. To identify mechanisms of resistance to BITEs, we collected serum, peripheral blood mononuclear cells, and ascites samples from patients with disease progression on MUC16-directed bispecific antibodies. Analysis of these samples showed downregulation of MUC16/CA125, elevated secretion of VEGF, and epithelial-to-mesenchymal transition in tumor cells. Interestingly, hypoxia was determined to be a driver of these changes. These findings were prospectively validated in ovarian cancer cell lines with CRISPR/Cas9 knockout of MUC16/CA125 and VEGF. Peripheral blood mononuclear cells from patients with disease progression were capable of effective cytolysis ex vivo, suggesting that resistance to therapy was primarily tumor driven. Restoration of MUC16/CA125 expression did not restore cytotoxicity in the presence of increased VEGF secretion. Combination treatment with a VEGF inhibitor rescued cytotoxicity in hypoxia-conditioned ovarian cancer cell lines with preserved target antigen expression. Collectively, these data outline a link between hypoxia and the development of resistance to BITEs and posits inhibition of VEGF inhibition as a potentially important therapeutic intervention.

HPV-YAP1 oncogenic alliance drives malignant transformation of fallopian tube epithelial cells

Abstract High grade serous ovarian carcinoma (HGSOC) is the most common and aggressive ovarian malignancy. Accumulating evidence indicates that HGSOC may originate from human fallopian tube epithelial cells (FTECs), although the exact pathogen(s) and/or molecular mechanism underlying the malignant transformation of FTECs is unclear. Here we show that human papillomavirus (HPV), which could reach FTECs via retrograde menstruation or sperm-carrying, interacts with the yes-associated protein 1 (YAP1) to drive the malignant transformation of FTECs. HPV prevents FTECs from natural replicative and YAP1-induced senescence, thereby promoting YAP1-induced malignant transformation of FTECs. HPV also stimulates proliferation and drives metastasis of YAP1-transformed FTECs. YAP1, in turn, stimulates the expression of the putative HPV receptors and suppresses the innate immune system to facilitate HPV acquisition. These findings provide critical clues for developing new strategies to prevent and treat HGSOC.