Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment

Naoki Horikawa,Mana Taki,Ryusuke Murakami,Masaki Mandai,Masafumi Koshiyama,Masayo Ukita,Junzo Hamanishi,Kaoru Abiko,Ikuo Konishi,Yuko Hosoe,Tsukasa Baba,Noriomi Matsumura,Ken Yamaguchi

doi:10.1038/s41416-019-0725-x

Abstract

BackgroundThe mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy.MethodsThe frequencies of immune cell populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. The expression profiles of both the proteins and genes in the resistant tumours were analysed. The impact of granulocyte–monocyte colony-stimulating factor (GM-CSF) expression on myeloid-derived suppressor cell (MDSC) function in the resistant tumours was evaluated.ResultsWe found a marked increase and reduction in the number of Gr-1 + MDSCs and CD8 + lymphocytes in the resistant tumour, and the MDSCs preferentially infiltrated the hypoxic region. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. GM-CSF promoted migration and differentiation of MDSCs, which inhibited the CD8 + lymphocyte proliferation. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case.ConclusionsThe anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers.

Highlights

The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear
We treated lymphocyte-deficient mice with the combination of anti-VEGF and anti-granulocyte–monocyte colony-stimulating factor (GM-CSF) antibodies, and observed no discernible change in the efficiency of therapy in comparison with only anti-VEGF antibody treatment (Supplementary Fig. S5b). These results suggest that the resistance to anti-VEGF therapy is associated with GM-CSF-mediated expansion of myeloid-derived suppressor cell (MDSC) resulting in lymphocyte suppression
Effective ovarian cancer treatment requires overcoming the resistance to available therapeutic options such as bevacizumab and increasing the sensitivity of tumours to the same

Summary

Introduction

The mechanism of resistance development to anti-VEGF therapy in ovarian cancer is unclear. We focused on the changes in tumour immunity post anti-VEGF therapy. METHODS: The frequencies of immune cell populations and hypoxic conditions in the resistant murine tumours and clinical samples were examined. Protein array analysis showed upregulation of GM-CSF post anti-VEGF therapy. Anti-GM-CSF therapy improved the anti-VEGF therapy efficacy, which reduced the infiltrating MDSCs and increased CD8 + lymphocytes. In immunohistochemical analysis of clinical samples, GM-CSF expression and MDSC infiltration was enhanced in the bevacizumab-resistant case. CONCLUSIONS: The anti-VEGF therapy induces tumour hypoxia and GM-CSF expression, which recruits MDSCs and inhibits tumour immunity. Targeting the GM-CSF could help overcome the anti-VEGF therapy resistance in ovarian cancers. Elucidating the mechanism of resistance to anti-VEGF therapy in ovarian cancer and overcoming the same is urgently required

Methods

Results

Conclusion