HDAC3 inhibitors induce drug resistance by promoting IL-17 A production by T cells.
Hao Chen, Anqi Qin, Fan Xu, Shuai Guo, Ge Zhang, Aihong Zhang, WenTing Li, Feng Tian, Quanhui Zheng
Author Information
Hao Chen: Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China.
Anqi Qin: Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China.
Fan Xu: Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China.
Shuai Guo: Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China.
Ge Zhang: School of Basic Medical, Xingtai Medical College, Xingtai, 054000, China.
Aihong Zhang: Department of ICU, The Affiliated Hospital of North China University of Science and Technology, Tangshan, 063000, China.
WenTing Li: Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing, 100083, China.
Feng Tian: Department of Laboratory Animal Science, Health Science Center, Peking University, Beijing, 100083, China.
Quanhui Zheng: Hebei Key Laboratory for Chronic Diseases, Tangshan Key Laboratory for Preclinical and Basic Research on Chronic Diseases, School of Basic Medical Sciences, North China University of Science and Technology, Tangshan, 063210, China. 1078209929@qq.com.
HDAC3 has been demonstrated to play a crucial role in the progression of various tumors and the differentiation and development of T cells. However, its impact on peripheral T cells in the development of murine lung cancer remains unclear. In this experiment, a subcutaneous lung tumor model was established in C57BL/6 mice, and tumor-bearing mice were treated with the specific inhibitor of HDAC3, RGFP966, at different doses to observe changes in tumor size. Additionally, a lung tumor model was established using hdac3cd4cre mice to investigate its mechanism. Mice injected with 10 mg/kg RGFP966 had the smallest tumor volume, while those injected with 30 mg/kg RGFP966 had the largest tumors. Flow cytometry analysis revealed that the expression of HDAC3 in splenic T cells was reduced in all groups of mice, while IFN-�� and IL-17 A were increased. Moreover, the expression of granzyme B and perforin in splenic CD8 T cells was increased in all groups of mice. Compared to the use of 30 mg/kg RGFP966 alone, the combination with anti-IL-17 A mAb reduced the infiltration of Neutrophils and exhausted T cells in mouse tumors, thereby impeding tumor development. These findings demonstrate that the use of RGFP966 or T cell-specific loss of hdac3 promotes the expression of IL-17 A in splenic T cells, leading to tumor resistance and providing insights for clinical treatment.
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