Objectives The beneficial effects of vascular endothelial growth factor A (VEGF-A) inhibitor are only observed in a subset of patients with advanced ovarian cancer. The lack of response of VEGF-A inhibitors is thought to be related with the immunosuppressive microenvironment; however, this is still controversial. A better understanding of the underlying mechanism of VEGF-A inhibitor (Bevacizumab)-mediated the immune escape could benefit the development of therapeutic regimens for patients with ovarian cancer.
Methods The polarization of tumor-associated macrophages (TAMs), IFN-γ secretion of macrophages and ovarian cancer cells, PD-L1 expression in ovarian cancer cells, and phagocytic function of macrophages after Bevacizumab intervention were examined. In addition, the efficacy of combined Bevacizumab with anti-PD-1 antibody (aPD-1) was evaluated in a murine ovarian cancer model.
Results We first identified that Bevacizumab stimulated IFN-γ secretion from macrophages and ovarian cancer cells. Moreover, we demonstrated that Bevacizumab upregulated PD-L1 expression in an IFN-γ-PI3K-NF-κB-dependent manner in ovarian cancer. Interestingly, although Bevacizumab elicited antitumor immunity by inducing macrophage polarization to an M1 phenotype via elevated IFN-γ secretion, the phagocytic function of macrophages was suppressed by upregulated PD-1 expression in macrophages. Furthermore, Bevacizumab combined with an aPD-1 significantly decreased the tumor burden and prolonged survival time in mice with ovarian cancer.
Conclusions Here, we demonstrated a dual role of IFN-γ induced by Bevacizumab in ovarian cancer. Specifically, IFN-γ promoted immune activation in terms of M1 polarization and immune suppression through PD-L1/PD-1 upregulation. The combination of Bevacizumab and aPD-1 improved the local immune status and provided a promising novel therapeutic regimen against ovarian cancer.
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