Pre-treatment of cabozantinib prior to hypofractionated radiotherapy increases immunomodulatory effects and tumor size reduction in a 4T1 breast cancer murine model.

Radiotherapy is one of the treatments used in breast cancer, which, in addition to immunomodulatory effects, causes immunosuppressive effects such as the increase in myeloid-derived suppressor cells (MDSCs). Cabozantinib is a multikinase inhibitor that targets multiple tyrosine kinases and has been shown to reduce MDSCs. This study aimed to combine radiotherapy with cabozantinib to improve treatment efficacy and promote a more favorable tumor microenvironment for the antitumor immune response. The 4T1 breast cancer cell line was injected into the flanks of BALB/c mice. Tumor-bearing mice were treated with a defined oral dose of cabozantinib and hypofractionated radiotherapy (2 × 10 Gy). Mice in different study groups were examined for the frequencies of TCD8+, TCD4+, Treg, MQ, and MDSC in tumor tissue, spleen, and tumor-draining lymph node by flow cytometry. Besides, the expression level of PD-L1 on tumor cells was checked by flow cytometry. Tumor size and survival of treated mice were also compared with those of the control group. Cabozantinib combined with radiotherapy, and especially cabozantinib in the early days of tumor induction, caused changes in the abundance of immune system cells, including an increase in the abundance of CD8 + T cells, an increase in the ratio of M1/M2 macrophages, and a decrease in Treg cells. Cabozantinib alone reduced the population of MDSC cells, and the population of these cells also decreased in the combination therapy group; however, this difference was not statistically significant. Combining cabozantinib with radiotherapy increased PD-L1 expression on the surface of tumor cells. Finally, combination therapy reduced tumor size and increased survival in mice. Our results showed that combining radiotherapy and cabozantinib reduced 4T1 tumor growth and enhanced anti-cancer immunomodulatory effects.