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EPV195/#37 VEGF-A inhibitor induced tumor-associated macrophage reprogramming and PD-L1 overexpression via a dual role of IFN-Γ in ovarian cancer
  1. C Li1,2,
  2. J Peng1,2,
  3. Y Li3,
  4. C Sun1,2,
  5. Z Zhang4,
  6. L Liu1,2,
  7. S Yao1,3,
  8. Y Li1,2 and
  9. K Song1,2
  1. 1Qilu Hospital of Shandong University, Gynecology Oncology Key Laboratory, Jinan, China
  2. 2Qilu Hospital, Cheeloo College of Medicine, Shandong University, Obstetrics and Gynecology, Jinan, China
  3. 3School of Medicine, Cheeloo College of Medicine, Shandong University, Obstetrics and Gynecology, Jinan, China
  4. 4Beijing Chao-Yang Hospital, Capital Medical University, Obstetrics and Gynecology, Beijing, China


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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