Translational Therapeutics

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

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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.


The 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.


We 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.


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.

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Fig. 1: Anti-VEGF therapy induces MDSCs and decreases CD8+lymphocytes in tumour.
Fig. 2: Anti-VEGF therapy induces tumour hypoxia and attracts MDSCs.
Fig. 3: Expression of GM-CSF is upregulated in a-VEGF abs-treated tumour.
Fig. 4: Upregulation of GM-CSF expression under hypoxia is mediated via the NF-κB pathway.
Fig. 5: The impact of GM-CSF signals on MDSC migration and differentiation.
Fig. 6: A-GM-CSF abs enhances the efficacy of a-VEGF abs against HM-1 tumours via lymphocyte activation.


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We thank Hana Ishiyama for her great technical assistance. We also thank Genentech for their gift of anti-mouse VEGF antibody.

Author information

Conceptualisation, N.H., K.A., N.M., T.B. and J.H.; methodology, N.H., K.A., N.M., T.B. and J.H.; investigation, N.H., R.M., M.U. and Y.H.; formal analysis, N.H. and R.M.; writing—original draft, N.H. and K.A.; writing—review and editing, K.A., N.M., T.B., J.H., K.Y., R.M. and M.T.; funding acquisition, K.A., N.M., T.B., J.H., M.K. and I.K.; supervision, I.K. and M.M.

Correspondence to Kaoru Abiko.

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The Ethics Committee of Kyoto University Hospital has approved the protocol for this research. The protocol also conforms to the provisions of the Declaration of Helsinki. All animal experiments were performed in accordance with the Guidelines for Proper Conduct of Animal Experiments announced by Science Council of Japan.

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Not applicable.

Data availability

Microarray datasets for this work are accessible on Gene Expression Omnibus website. (

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The authors declare no competing interests.

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This work was supported by a Grant-in Aid for Scientific Research (KAKENHI) from the Ministry of Education, Culture, Sports, Science and Technology, Japan (MEXT, No. 15H04309).

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Horikawa, N., Abiko, K., Matsumura, N. et al. Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment. Br J Cancer (2020) doi:10.1038/s41416-019-0725-x

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