Targeting MELK improves PD-1 blockade efficiency in cervical cancer via enhancing antitumor immunity

Abstract

The balance between T helper 1 (Th1) and T helper 2 (Th2) has a critical function in determining intratumoral immune response and anti-PD-1 immunotherapy. The level of maternal embryonic leucine zipper kinase (MELK) is reported to correlate with infiltration of immune cells in cancers, but the underlying molecular mechanism is not clarified. In the present study, we aimed to elucidate the potential function of MELK in cervical cancer. We found that MELK was upregulated and played an oncogenic role in cervical cancer. MELK overexpression shifted Th1/Th2 balance toward Th2 predisposition in mouse cervical tumors in vivo and naive T cells from human PBMCs in vitro, whereas MELK knockdown exhibited opposite effects. MELK overexpression activated NF-κB signaling and promoted IL-6 secretion by cervical cancer cells. Depletion of IL-6 by neutralization antibodies abrogated the influence of MELK on Th1/Th2 balance. In addition, MELK modulated the antitumor activity of cytotoxic CD8+ T cells in cervical tumors, but depletion of Th2 cells by IL-4 neutralization abrogated this effect. Finally, MELK overexpression conferred tolerance to PD-1 blockade in cervical tumors, whereas targeting MELK by OTSSP167 significantly enhanced PD-1 blockade efficiency. Our data elucidated a novel role of MELK in regulating Th1/Th2 balance and anti-PD-1 immunotherapy in cervical cancer.

Keywords

• MT: Regular Issue
• cervical cancer
• MELK
• PD-1 blockade
• Th1/Th2 polarization
• NF-κB