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Evaluating the Angiogenetic Properties of Ovarian Cancer Stem-Like Cells using the Three-Dimensional Co-Culture System, NICO-1
Published on: December 5, 2020
Anti-VEGF therapy resistance in ovarian cancer is caused by GM-CSF-induced myeloid-derived suppressor cell
Naoki Horikawa1, Kaoru Abiko2,3, Noriomi Matsumura4
1Department of Gynecology and Obstetrics, Kyoto University Graduate School of Medicine, Kyoto, Japan.
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.
Insights
Anti-VEGF therapy resistance in ovarian cancer is linked to increased myeloid-derived suppressor cells (MDSCs) and tumor hypoxia. Targeting granulocyte-macrophage colony-stimulating factor (GM-CSF) can overcome this resistance by restoring anti-tumor immunity.
Area of Science:
- Oncology
- Immunology
- Cancer Therapy
Background:
- The mechanisms driving resistance to anti-VEGF therapy in ovarian cancer remain poorly understood.
- This study investigates the alterations in tumor immunity following anti-VEGF treatment.
Purpose of the Study:
- To elucidate the changes in immune cell populations and tumor microenvironment in anti-VEGF resistant ovarian cancer.
- To evaluate the role of granulocyte-macrophage colony-stimulating factor (GM-CSF) in mediating resistance.
Main Methods:
- Analysis of immune cell frequencies and hypoxic conditions in resistant murine tumors and clinical samples.
- Examination of protein and gene expression profiles, including GM-CSF.
- Assessment of GM-CSF's impact on myeloid-derived suppressor cell (MDSC) function.
Main Results:
- Resistant tumors showed increased Gr-1+ MDSCs and decreased CD8+ lymphocytes, with MDSCs infiltrating hypoxic regions.
- Anti-VEGF therapy led to GM-CSF upregulation, promoting MDSC migration and inhibiting CD8+ T cell proliferation.
- Combined anti-GM-CSF and anti-VEGF therapy enhanced efficacy, reducing MDSCs and increasing CD8+ lymphocytes.
Conclusions:
- Anti-VEGF therapy induces tumor hypoxia and GM-CSF, which recruits MDSCs and suppresses anti-tumor immunity.
- Targeting GM-CSF presents a promising strategy to overcome anti-VEGF resistance in ovarian cancer.
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