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Artemisinin enhances the anti-tumor immune response in 4T1 breast cancer T cells in vitro and in vivo
Yu Caoa,b, Yong-Hui Fengc, Li-Wei Gaod, Xiao-Ying Lib, Quan-Xiu Jinb,e, Yu-Ying Wangb,e, Ying-Ying Xub, Feng Jinb, Shi-Long Lua,f, Min-Jie Weia,
a Laboratory of Precision Oncology, China Medial University School of Pharmacy, Shenyang, Liaoning, China
b Department of Surgical Oncology and Breast Surgery, The First Aﬃliated Hospital of China Medical University, Shenyang, Liaoning, China
c Department of Laboratory Medicine, The First Aﬃliated Hospital of China Medical University, Shenyang, Liaoning, China
d Department of Radiation Oncology, China Japan Friendship Hospital, Beijing, China
e Department of Breast Surgery, Liaoning Cancer Hospital, Shenyang, Liaoning, China
f Department of Otolaryngology, University of Colorado School of Medicine, Aurora, CO 80045, USA
Background: Breast cancer is a prominent cause of death among women worldwide. Recent studies have de-monstrated that artemisinin (ART) displays anti-tumor activity. Using a mouse breast cancer model, we in-vestigated the eﬀects of ART in vitro and in vivo to determine how it influences the anti-tumor immune response. Methods: We measured the proliferation and apoptosis of 4T1 cells in vitro after ART treatment by MTT assay and FACS. To examine the eﬀects of ART in vivo, tumor volumes and survival rates were measured in 4T1 tumor-bearing mice. FACS was used to determine the frequencies of Tregs, MDSCs, CD4+ IFN-γ+ T cells, and CTLs in the tumors and spleens of the mice. mRNA levels of the transcription factors T-bet and FOXP3 and cytokines IFN-γ, TNF-α, TGF-β, and IL-10 were also determined by real-time RT-PCR. ELISA was used to measure TGF-β protein levels in the cell culture supernatants.
Results: ART supplementation significantly increased 4T1 cell apoptosis and decreased TGF-β levels in vitro. ART also impeded tumor growth in 4T1 TB mice and extended their survival. MDSC and Treg frequencies sig-nificantly decreased in the 4T1 TB mice after ART treatment while CD4+ IFN-γ+ T cells and CTLs significantly increased. ART significantly increased T-bet, IFN-γ, and TNF-α mRNA levels within the tumor and significantly decreased TGF-β mRNA levels.
Conclusion: ART supplementation hindered 4T1 tumor growth in vivo by promoting T cell activation and quelling immunosuppression from Tregs and MDSCs in the tumor.
Breast cancer remains one of the leading causes of cancer-related death in women worldwide . Although considerable progress has been made in treating breast cancer and prolonging patient survival, the cancer often reoccurs [2,3]. Additionally, side eﬀects from these treatments can have many adverse eﬀects on the patients' quality of life [4,5]. A greater understanding of breast cancer metastasis and dis-covery of new drugs are essential for the development of novel treat-ment strategies to eradicate breast cancer.