PI3K alpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8(+)T cells and promoting fatty acid metabolism

doi:10.1136/jitc-2021-003093

	PI3K alpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8(+)T cells and promoting fatty acid metabolism
	Sun, Pu 1,2; Zhang, Xi 1; Wang, Rong-Jing 2,3; Ma, Qing-Yang 3; Xu, Lan 1; Wang, Yi 1; Liao, Hui-Ping 3; Wang, Hai-Long 3; Hu, Lan-Dian 3; Kong, Xiangyin 2,3
刊名	JOURNAL FOR IMMUNOTHERAPY OF CANCER
	2021
卷号	9 期号:8 页码:16
关键词	tumor microenvironment immunomodulation immunologic memory lymphocytes tumor-infiltrating macrophages
DOI	10.1136/jitc-2021-003093
通讯作者	Kong, Xiangyin(xykong@sibs.ac.cn) ; Ding, Jian(jding@simm.ac.cn) ; Meng, Ling-Hua(lhmeng@simm.ac.cn)
英文摘要	Background The phosphatidylinositol 3-kinase (PI3K) is frequently hyperactivated in cancer and plays important roles in both malignant and immune cells. The effect of PI3K alpha inhibitors on the tumor microenvironment (TME) remains largely unknown. Here, we investigated the modulation of the TME by a clinical PI3K alpha-specific inhibitor CYH33. Methods The activity of CYH33 against a panel of murine tumors in the immune-competent context or athymic mice was detected. Single-cell RNA sequencing and multi-parameter flow cytometry were performed to determine the immune profiling of TME. The effect of CYH33 on immune cells was conducted with primary murine cells. Results CYH33 exhibited more potent antitumor activity in immune-competent context. CYH33 enhanced the infiltration and activation of CD8(+)T and CD4(+)T cells, while attenuating M2-like macrophages and regulatory CD4(+)T cells. Increase in memory T cells was confirmed by the induction of long-term immune memory on CYH33 treatment. Mechanistically, CYH33 relieved the suppressed expansion of CD8(+)T cells via preferential polarization of the macrophages to the M1 phenotype. CYH33 promoted fatty acid (FA) metabolism in the TME, while FA enhanced the activity of CD8(+)T cells in vitro. The combination of CYH33 with the FA synthase (FASN) inhibitor C75 synergistically inhibited tumor growth with enhanced host immunity. Conclusions CYH33 induces immune activation and synergizes with FASN inhibitor to further promote the antitumor immunity, which gains novel insights into how PI3K inhibitors exert their activity by modulating TME and provides a rationale for the concurrent targeting of PI3K and FASN in breast cancer treatment.
资助项目	National Natural Science Foundation of China[81973345] ; National Natural Science Foundation of China[81773760] ; 'Personalized Medicines-Molecular Signature-based Drug Discovery and Development', Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12010204] ; 'Personalized Medicines-Molecular Signature-based Drug Discovery and Development', Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020111] ; National Key Research and Development Program of China[2017YFA0103501] ; STS Program of Chinese Academy Sciences[KFJ-STS-QYZD-187]
WOS关键词	REGULATORY T-CELLS ; GENE-EXPRESSION ; PI3K PATHWAY ; SYNTHASE ; IDELALISIB ; PI3K-GAMMA ; GROWTH ; BETA
WOS研究方向	Oncology ; Immunology
语种	英语
出版者	BMJ PUBLISHING GROUP
WOS记录号	WOS:000683835300001
内容类型	期刊论文
源URL	[http://119.78.100.183/handle/2S10ELR8/298079]
专题	中国科学院上海药物研究所
通讯作者	Kong, Xiangyin; Ding, Jian; Meng, Ling-Hua
作者单位	1.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, Shanghai, Peoples R China 2.Univ Chinese Acad Sci, Beijing, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Nutr & Hlth, Key Lab Tissue Microenvironm & Tumor, Shanghai, Peoples R China 4.Chinese Acad Sci, Shanghai Inst Mat Med, Div Antitumor Pharmacol, State Key Lab Drug Res, Shanghai, Peoples R China
推荐引用方式 GB/T 7714	Sun, Pu,Zhang, Xi,Wang, Rong-Jing,et al. PI3K alpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8(+)T cells and promoting fatty acid metabolism[J]. JOURNAL FOR IMMUNOTHERAPY OF CANCER,2021,9(8):16.
APA	Sun, Pu.,Zhang, Xi.,Wang, Rong-Jing.,Ma, Qing-Yang.,Xu, Lan.,...&Meng, Ling-Hua.(2021).PI3K alpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8(+)T cells and promoting fatty acid metabolism.JOURNAL FOR IMMUNOTHERAPY OF CANCER,9(8),16.
MLA	Sun, Pu,et al."PI3K alpha inhibitor CYH33 triggers antitumor immunity in murine breast cancer by activating CD8(+)T cells and promoting fatty acid metabolism".JOURNAL FOR IMMUNOTHERAPY OF CANCER 9.8(2021):16.