2. Academic Validation
  3. Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell recruitment

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

  • Br J Cancer. 2020 Mar;122(6):778-788. doi: 10.1038/s41416-019-0725-x.
Naoki Horikawa 1,  Kaoru Abiko 2 3,  Noriomi Matsumura 4,  Tsukasa Baba 5,  Junzo Hamanishi 1,  Ken Yamaguchi 1 6,  Ryusuke Murakami 1,  Mana Taki 1,  Masayo Ukita 1,  Yuko Hosoe 1,  Masafumi Koshiyama 7,  Ikuo Konishi 6,  Masaki Mandai 1
Affiliations

Affiliations

  • 1 Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
  • 2 Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan. kaoruvc@kuhp.kyoto-u.ac.jp.
  • 3 Department of Obstetrics and Gynecology, National Hospital Organization, Kyoto medical center, Kyoto, Japan. kaoruvc@kuhp.kyoto-u.ac.jp.
  • 4 Department of Obstetrics and Gynecology, Kindai University Faculty of Medicine, Osaka, Japan.
  • 5 Department of Obstetrics and Gynecology, Iwate Medical University School of Medicine, Iwate, Japan.
  • 6 Department of Obstetrics and Gynecology, National Hospital Organization, Kyoto medical center, Kyoto, Japan.
  • 7 The University of Shiga Prefecture, Shiga, Japan.
PMID: 31932754 DOI: 10.1038/s41416-019-0725-x
Abstract

Background: 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. 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.

Results: 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.

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.

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