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A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses

文献类型：期刊论文

作者Shi, Wenqiang3,4; Xu, Wei2; Song, Luyao3,4; Zeng, Qiongya3,4; Qi, Gen3,4; Qin, Ying3,4; Li, Zhikun2; Liu, Xianglei5; Jiao, Zheng6; Zhao, Yonggang7
刊名MOLECULAR THERAPY
出版日期2024-12-04
卷号32期号:12页码:4482-4496
ISSN号1525-0016
DOI10.1016/j.ymthe.2024.10.021
通讯作者Liu, Nan(liunan@simm.ac.cn) ; Lu, Huili(roadeer@sjtu.edu.cn)
英文摘要It is a challenge to invigorate tumor-infiltrating lymphocytes without causing immune-related adverse events, which also stands as a primary factor contributing to resistance against cancer immunotherapies. Interleukin (IL)-15 can potently promote expansion and activation of T cells, but its clinical use has been limited by dose-limiting toxicities. In this study, we develop a tumor-conditional IL-15 (pro-IL-15), which masks IL-15 with steric hindrance caused by Fc fragment and IL-15Ra-sushi domain. Upon reaching the tumor site, it can be cleaved by tumor-associated proteases to release an IL-15 superagonist, resulting in potent antitumor activities. Systemic delivery of pro-IL-15 demonstrates significantly reduced toxicity but uncompromised antitumor efficacy. Pro-IL-15 can yield better effectors and vitalize terminally exhausted CD8+ T cells to overcome checkpoint blockade resistance. Moreover, pro-IL-15 promotes chemotaxis and activation of adoptive T cells, leading to eradication of advanced solid tumors and durable cures. Furthermore, pro-IL-15 shows promise for synergizing with other immunotherapies like IL-12 and oncolytic virus by improving the CD8/Treg ratio and interferon-g levels, resulting in substantial regression of both local and metastatic cold tumors. Collectively, our results suggest that pro-IL-15 represents a compelling strategy for overcoming resistance to current immunotherapies while avoiding toxicities.
WOS关键词CD4(+) T-CELLS ; REGULATES HOMEOSTASIS ; COMPLEX
资助项目Fundamental Research Funds for the Central Universities[YG2023ZD284] ; Natural Science Foundation of Chongqing[2022NSCQ-MSX2319] ; Science and Technology Commission of Shanghai Municipality[21S11906300] ; Science and Technology Commission of Shanghai Municipality[23ZR1431800] ; National Key Laboratory of Lead Druggability Research (Shanghai Institute of Pharmaceutical Industry Co. Ltd.)[NKLKF2023001] ; National Natural Science Foundation of China[82404500]
WOS研究方向Biotechnology & Applied Microbiology ; Genetics & Heredity ; Research & Experimental Medicine
语种英语
WOS记录号WOS:001373753300001
出版者CELL PRESS
源URL[http://119.78.100.183/handle/2S10ELR8/315031]  
专题中国科学院上海药物研究所
通讯作者Liu, Nan; Lu, Huili
作者单位1.Shanghai Jiao Tong Univ, Chongqing Res Inst, Chongqing 401135, Peoples R China
2.Shanghai Jiao Tong Univ, Sch Med, Tongren Hosp, Dept Orthoped, 1111 XianXia Rd, Shanghai 200336, Peoples R China
3.Shanghai Jiao Tong Univ, Engn Res Ctr Cell & Therapeut Antibody, Sch Pharm, Minist Educ, 800 Dongchuan Rd, Shanghai 200240, Peoples R China
4.Shanghai Jiao Tong Univ, Shanghai Frontiers Sci Ctr Drug Target Identificat, Sch Pharm, Natl Key Lab Innovat Immunotherapy, 800 Dongchuan Rd, Shanghai 200240, Peoples R China
5.China State Inst Pharmaceut Ind, Natl Key Lab Lead Druggabil Res, 285 Gebaini Rd, Shanghai 201203, Peoples R China
6.Shanghai Jiao Tong Univ, Shanghai Chest Hosp, Sch Med, 241 Huaihai West Rd, Shanghai 200030, Peoples R China
7.Suzhou HKeyBio Co Ltd, 218 Xinghu St, Suzhou 215004, Peoples R China
8.Chinese Acad Sci, Shanghai Inst Mat Med, 555 Zuchongzhi Rd, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Shi, Wenqiang,Xu, Wei,Song, Luyao,et al. A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses[J]. MOLECULAR THERAPY,2024,32(12):4482-4496.
APA Shi, Wenqiang.,Xu, Wei.,Song, Luyao.,Zeng, Qiongya.,Qi, Gen.,...&Lu, Huili.(2024).A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses.MOLECULAR THERAPY,32(12),4482-4496.
MLA Shi, Wenqiang,et al."A tumor-conditional IL-15 safely synergizes with immunotherapy to enhance antitumor immune responses".MOLECULAR THERAPY 32.12(2024):4482-4496.

入库方式： OAI收割

来源：上海药物研究所

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