High-Dose Sunitinib Accelerates Triple-Negative Breast Cancer Metastasis by Modulating an Immunosuppressive Microenvironment: A Preclinical 4T1 Model Study.

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.