Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling

doi:10.1016/j.chembiol.2022.05.012

	Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling
	Geng, Chen-Lu1,2 ; Chen, Jun-Yi2 ; Song, Tian -Yu 2,3; Jung, Jae Hyung 4; Long, Min 1,2; Song, Min -Fang2 ; Ji, Tong 5; Min, Byung Soh 6; Lee, Jin Gu 7; Peng, Bo2 ; Pu, Yi-Sheng2 ; Fan, Hong-Jie2 ; Hao, Piliang2 ; Zhou, Qi 1; Shin, Eui-Cheol 4; Cang, Yong2
	2022-08-18
发表期刊	CELL CHEMICAL BIOLOGY (IF:6.6[JCR-2023],8.2[5-Year])
ISSN	2451-9456
EISSN	2451-9448
卷号	29 期号:8
发表状态	已发表
DOI	10.1016/j.chembiol.2022.05.012
摘要	Programmed cell death protein 1 (PD-1) checkpoint blockade therapy requires the CD28 co-stimulatory re-ceptor for CD8(+) T cell expansion and cytotoxicity. However, CD28 expression is frequently lost in exhausted T cells and during immune senescence, limiting the clinical benefits of PD-1 immunotherapy in individuals with cancer. Here, using a cereblon knockin mouse model that regains in vivo T cell response to lenalidomide, an immunomodulatory imide drug, we show that lenalidomide reinstates the anti-tumor activity of CD28-defi-cient CD8(+) T cells after PD-1 blockade. Lenalidomide redirects the CRL4(Crbn) ubiquitin ligase to degrade Ikzf1 and Ikzf3 in T cells and unleashes paracrine interleukin-2 (IL-2) and intracellular Notch signaling, which collec-tively bypass the CD28 requirement for activation of intratumoral CD8+ T cells and inhibition of tumor growth by PD-1 blockade. Our results suggest that PD-1 immunotherapy can benefit from a lenalidomide combina-tion when treating solid tumors infiltrated with abundant CD28- T cells.
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收录类别	SCI ; SCIE
语种	英语
资助项目	National Natural Science Foundation of China["31970671","31671334","82003803"] ; Shanghai Science and Technology Commission[18JC1413900]
WOS研究方向	Biochemistry & Molecular Biology
WOS类目	Biochemistry & Molecular Biology
WOS记录号	WOS:000860117400003
出版者	CELL PRESS
引用统计	被引频次：11[WOS] [WOS记录] [WOS相关记录]
文献类型	期刊论文
条目标识符	https://kms.shanghaitech.edu.cn/handle/2MSLDSTB/229864
专题	生命科学与技术学院_PI研究组_仓勇组生命科学与技术学院_公共科研平台_组学分析平台生命科学与技术学院_硕士生生命科学与技术学院_博士生
通讯作者	Cang, Yong
作者单位	1.Zhejiang Univ, Life Sci Inst, Hangzhou, Zhejiang, Peoples R China 2.ShanghaiTech Univ, Sch Life Sci & Technol, 393 Middle Huaxia Rd, Shanghai 201210, Peoples R China 3.Chinese Acad Sci, Shanghai Inst Biol Sci, Shanghai, Peoples R China 4.Korea Adv Inst Sci & Technol, Grad Sch Med Sci & Engn, Daejeon, South Korea 5.Zhejiang Univ, Sch Med, Sir Run Run Shaw Hosp, Dept Gen Surg,Key Lab Laparoscop Tech Res Zhejiang, Hangzhou, Zhejiang, Peoples R China 6.Yonsei Univ, Coll Med, Yonsei Canc Ctr, Dept Surg, Seoul, South Korea 7.Yonsei Univ, Coll Med, Severance Hosp, Dept Thorac & Cardiovasc Surg, Seoul, South Korea
第一作者单位	生命科学与技术学院
通讯作者单位	生命科学与技术学院
推荐引用方式 GB/T 7714	Geng, Chen-Lu,Chen, Jun-Yi,Song, Tian -Yu,et al. Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling[J]. CELL CHEMICAL BIOLOGY,2022,29(8).
APA	Geng, Chen-Lu.,Chen, Jun-Yi.,Song, Tian -Yu.,Jung, Jae Hyung.,Long, Min.,...&Cang, Yong.(2022).Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling.CELL CHEMICAL BIOLOGY,29(8).
MLA	Geng, Chen-Lu,et al."Lenalidomide bypasses CD28 co-stimulation to reinstate PD-1 immunotherapy by activating Notch signaling".CELL CHEMICAL BIOLOGY 29.8(2022).