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High-Dose Sunitinib Accelerates Triple-Negative Breast Cancer Metastasis by Modulating an Immunosuppressive
Chen Liu1, Junsheng Xue1, Tianyu Wang1
1Department of Pharmaceutics, School of Pharmaceutical Sciences, Peking University Health Science Center, Beijing, 100191, China.
Background:
Sunitinib (SUN), a multi-targeted anti-angiogenic tyrosine kinase inhibitor, could inhibit tumor growth and affect tumor microenvironment (TME). However, survival benefit for triple-negative breast cancer (TNBC) patients was limited and the drug resistance probably related to its pro-metastatic effect. The association between metastasis progression and SUN dosage, also the underlying mechanism still remains unclear. Herein, we illustrated the biphasic effect of SUN on metastasis attributed to divergent TME conditions modulated by different therapeutic SUN doses.
Methods:
4T1 murine TNBC cells and orthotopic allograft model were used. The effect of different doses of SUN on tumor progression was assessed on tumor-bearing mice. Mechanistically, scratch wound assay and Transwell were used to examine the motility of 4T1 cells in vitro. Flow cytometry, blood routine and combined drug evaluation were conducted to explore the TME-related pro-metastatic mechanism in vivo.
Results:
Within therapeutic range, only high-dose SUN demonstrated pro-metastatic effect and have no benefit on prolonging the mice survival. Notably, it induced an immunosuppressive TME in multi-sites attenuating both innate and adaptive immune response rather than altering 4T1 cells motility. Consistent with the PD-L1 mediated T-cell inhibition in primary TME, co-administration of an anti-programmed death-1 (PD-1) monoclonal antibody reversed the high-dose SUN-induced increase in metastasis.
Conclusions:
Our data critically elaborated the impact of therapeutic dosage of SUN on tumor progression and treatment outcome. Our finding emphasized the biphasic effect under diverse SUN dosages and potentially informed optimized therapeutic regimens for TNBC patients.
Insights
High-dose sunitinib (SUN) promotes triple-negative breast cancer (TNBC) metastasis by suppressing the immune microenvironment, not by affecting cancer cell motility. Combining SUN with anti-PD-1 therapy may overcome this resistance.
Area of Science:
- Oncology
- Immunology
- Pharmacology
Background:
- Sunitinib (SUN), a tyrosine kinase inhibitor, affects tumor microenvironment (TME) but shows limited benefit in triple-negative breast cancer (TNBC).
- Drug resistance in TNBC may be linked to SUN's pro-metastatic effects, with unclear dose-dependency and mechanisms.
- This study investigates the biphasic effect of SUN on metastasis driven by TME alterations at different doses.
Purpose of the Study:
- To elucidate the dose-dependent effect of sunitinib on triple-negative breast cancer (TNBC) metastasis.
- To investigate the underlying mechanisms of sunitinib-induced metastasis, focusing on the tumor microenvironment (TME).
- To explore potential therapeutic strategies to overcome sunitinib resistance in TNBC.
Main Methods:
- Utilized 4T1 murine TNBC cells and an orthotopic allograft model to assess tumor progression.
- Examined 4T1 cell motility in vitro using scratch wound and Transwell assays.
- Analyzed TME changes in vivo via flow cytometry, blood routine analysis, and combined drug evaluations.
Main Results:
- High-dose sunitinib (SUN) exhibited a pro-metastatic effect in mice without improving survival.
- High-dose SUN induced an immunosuppressive TME, impairing innate and adaptive immune responses.
- Co-administration with anti-PD-1 antibody reversed high-dose SUN-induced metastasis, suggesting PD-L1 mediated T-cell inhibition.
Conclusions:
- Therapeutic dosage of SUN significantly impacts TNBC progression and treatment outcomes.
- SUN demonstrates a biphasic effect on metastasis, dependent on dosage and TME modulation.
- Findings suggest optimized therapeutic regimens involving SUN dosage and immunotherapy for TNBC patients.
