ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8(+) cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy

	ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8(+) cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy
	Li, CY; Li, WY; Xiao, J; Jiao, SZ; Teng, F; Xue, SJ; Zhang, C; Sheng, C; Leng, QB; Rudd, CE
刊名	EMBO MOLECULAR MEDICINE
	2015
卷号	7 期号:6 页码:754-769
关键词	ADAP SKAP55 anti-tumor immunotherapy CsA CTL cytotoxicity PD-1
通讯作者	Wei, B (reprint author), Chinese Acad Sci, Wuhan Inst Virol, State Key Lab Virol, Wuhan, Peoples R China.,weibin@wh.iov.cn ; hongyanwang@sibcb.ac.cn
英文摘要	PD-1 negatively regulates CD8(+) cytotoxic T lymphocytes (CTL) cytotoxicity and anti-tumor immunity. However, it is not fully understood how PD-1 expression on CD8(+) CTL is regulated during anti-tumor immunotherapy. In this study, we have identified that the ADAP-SKAP55 signaling module reduced CD8(+) CTL cytotoxicity and enhanced PD-1 expression in a Fyn-, Ca2+-, and NFATc1-dependent manner. In DC vaccine-based tumor prevention and therapeutic models, knockout of SKAP55 or ADAP showed a heightened protection from tumor formation or metastases in mice and reduced PD-1 expression in CD8(+) effector cells. Interestingly, CTLA-4 levels and the percentages of tumor infiltrating CD4(+)Foxp3(+) Tregs remained unchanged. Furthermore, adoptive transfer of SKAP55-deficient or ADAP-deficient CD8(+) CTLs significantly blocked tumor growth and increased anti-tumor immunity. Pretreatment of wild-type CD8(+) CTLs with the NFATc1 inhibitor CsA could also downregulate PD-1 expression and enhance anti-tumor therapeutic efficacy. Together, we propose that targeting the unrecognized ADAP-SKAP55-NFATc1-PD-1 pathway might increase efficacy of anti-tumor immunotherapy.
学科主题	Research & Experimental Medicine
类目[WOS]	Medicine, Research & Experimental
关键词[WOS]	CHRONIC VIRAL-INFECTION ; MEDIATED INTEGRIN ACTIVATION ; CYCLOSPORINE-A ; CANCER-IMMUNOTHERAPY ; CELL-ACTIVATION ; ANTI-PD-L1 ANTIBODY ; PROGRAMMED DEATH-1 ; SIGNALING MODULE ; ADHESION ; TUMOR
收录类别	SCI
语种	英语
WOS记录号	WOS:000355686400006
内容类型	期刊论文
版本	出版稿
源URL	[http://202.127.25.143/handle/331003/71]
专题	上海生化细胞研究所_上海生科院生化细胞研究所
推荐引用方式 GB/T 7714	Li, CY,Li, WY,Xiao, J,et al. ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8(+) cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy[J]. EMBO MOLECULAR MEDICINE,2015,7(6):754-769.
APA	Li, CY.,Li, WY.,Xiao, J.,Jiao, SZ.,Teng, F.,...&Wang, HY.(2015).ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8(+) cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy.EMBO MOLECULAR MEDICINE,7(6),754-769.
MLA	Li, CY,et al."ADAP and SKAP55 deficiency suppresses PD-1 expression in CD8(+) cytotoxic T lymphocytes for enhanced anti-tumor immunotherapy".EMBO MOLECULAR MEDICINE 7.6(2015):754-769.