Zhongguo linchuang yanjiu (Mar 2024)
Immunotherapy effects of apatinib mesylate combined with toripalimab on triple-negative breast cancer mice
Abstract
Objective To investigate the application and effects of apatinib mesylate combined with programmed death receptor-1 (PD-1) monoclonal antibody (mAb)—toripalimab in immunotherapy for triple negative breast cancer (TNBC). Methods Among 40 female BALB/C mice, 8 mice were randomly selected as the blank group without tumor inoculation, and the remaining 32 mice were inoculated with 4T1 cells to establish TNBC models. They were randomly divided into toripalimab group (n=8, administered 10 mg/kg of toripalimab through the tail vein on the 3rd, 6th, and 9th day)， apatinib group (n=8, received 60 mg/kg of apatinib mesylate by gavage daily for 21 consecutive days), combination group (n=8, administration route and dose of apatinib mesylate and toripalimab were the same as those of each single drug group), and model group (n=8, administered normal saline with same volume as administration groups by gavage and tail vein injection at the same time points). The changes of tumor weight and tumor volume in mice were monitored, the pathological changes of tumor in situ and liver/lung metastases in each group were analyzed by HE method, and the markers expressions of CD8+T lymphocytes, myeloid-derived suppressor cells (MDSCs), M2 tumor-associated macrophages (M2-TAMs) and regulatory T cells (Tregs) in the tumor tissues of mice in each group were analyzed by flow cytometry. Results (1) in situ tumors: the volume of in situ tumors in all three administration groups of mice was smaller than that in model group (P＜0.01), while that was smaller in combined group compared with apatinib group and toripalimab group (P＜0.01). Based on model group, the tumor inhibition rates of apatinib group, toripalimab group and combination group increased by (20.3±0.9)%, (24.5±1.2)% and (52.9±0.8)%, respectively, with the highest in combination group (F=997.528, P＜0.01). Pathology showed that the apoptosis phenomenon of in situ tumor cells in combination group was the most significant. (2) Lung/liver metastases: the pathology showed that combination group had the smallest area of lung metastases and the fewest number of liver metastases. (3) Immune cells: compared with the other three groups, the proportion of immune promoting cells (CD8+T cells) in the tumor tissue of combination group significantly increased (P＜0.05), while the proportion of immunosuppressive cells (MDSCs, M2-TAMs, and Tregs cells) significantly reduced (P＜0.05). Conclusion The combination of apatinib mesylate and toripalimab in the treatment of TNBC mice may inhibit the growth of in situ tumor and the formation of lung/liver metastasis formation, and significantly improve the immune efficacy by increasing the proportion of intratumoral immune-promoting cells and reducing the proportion of immunosuppressive cells.
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