17-hydroxy-jolkinolide B potentiated CTLA4ab therapy through targeting tumor suppression and immune activation by downregulating PD-L1 expression in lung adenocarcinoma.

Abstract

Background: 17-hydroxy-jolkinolide B (HJB) is a natural diterpenoid compound derived from plants of the Euphorbiaceae family that has anticancer properties against various types of tumors. However, its action and underlying mechanism in lung adenocarcinoma (LUAD) progression remain largely unknown. Thus, this research aimed to explore the role of HJB in LUAD pathogenesis and its clinical significance in tumor therapy.

Methods: Cell Counting Kit-8 (CCK-8) assay, colony formation assay, and scratch wound-healing assay were utilized to evaluate the effect of HJB on proliferation, colony formation, and migration of LUAD cells in vitro. The syngeneic and xenograft tumor models were used to evaluate the anti-tumor activity of HJB in combination with cytotoxic T-lymphocyte antigen 4 antibody (CTLA4ab) on LUAD in vivo. In addition, quantitative real-time polymerase chain reaction (qPCR) and western blotting analyses were used to analyze the expression of programmed death ligand 1 (PD-L1). Lentiviral transduction and transfection were used to explore the related mechanism.

Results: Experimental data demonstrated that HJB inhibited cell viability, colony formation, and migration of murine and human LUAD cells in vitro. The syngeneic and xenograft tumor models indicated that HJB possessed a remarkable anti-tumor activity in vivo and potentiated immune checkpoint blockades (ICBs) therapy. Moreover, PD-L1 might serve as a novel target in HJB-suppressed lung cancer.

Conclusions: By targeting PD-L1, HJB inhibited tumor cell proliferation and colony formation, as well as migration ability in vitro and in vivo. Besides, HJB enhanced CTLA4ab therapy and may be a potential agent for LUAD therapy.