IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases

被引:115
作者
Zhao, Yang [1 ,2 ]
Chen, Jiangqing [3 ]
Andreatta, Massimo [4 ,5 ]
Feng, Bing [1 ,2 ]
Xie, Yu-Qing [1 ]
Wenes, Mathias [4 ]
Wang, Yi [1 ,2 ]
Gao, Min [1 ]
Hu, Xiaomeng [1 ]
Romero, Pedro [4 ]
Carmona, Santiago [4 ,5 ]
Sun, Jie [3 ]
Guo, Yugang [1 ,2 ,6 ,7 ]
Tang, Li [1 ,2 ]
机构
[1] Ecole Polytech Fed Lausanne, Inst Bioengn, Lausanne, Switzerland
[2] Ecole Polytech Fed Lausanne, Inst Mat Sci & Engn, Lausanne, Switzerland
[3] Zhejiang Univ, Bone Marrow Transplantat Ctr, Dept Cell Biol, Affiliated Hosp 1,Sch Med, Hangzhou, Peoples R China
[4] Univ Lausanne, Dept Oncol, Lausanne, Switzerland
[5] Swiss Inst Bioinformat, Lausanne, Switzerland
[6] Zhejiang Univ, Inst Drug Metab & Pharmaceut Anal, Coll Pharmaceut Sci, Hangzhou, Peoples R China
[7] Zhejiang Univ, Natl Key Lab Adv Drug Delivery & Release Syst, Hangzhou, Peoples R China
基金
欧洲研究理事会; 瑞士国家科学基金会; 中国国家自然科学基金;
关键词
EXHAUSTION; ACTIVATION; MATURATION; SIGNATURE; PROMOTES; EFFICACY; SUBSET;
D O I
10.1038/s41587-023-02060-8
中图分类号
Q81 [生物工程学(生物技术)]; Q93 [微生物学];
学科分类号
071005 ; 0836 ; 090102 ; 100705 ;
摘要
The success of chimeric antigen receptor (CAR) T cell therapy in treating several hematopoietic malignancies has been difficult to replicate in solid tumors, in part because of T cell exhaustion and eventually dysfunction. To counter T cell dysfunction in the tumor microenvironment, we metabolically armored CAR T cells by engineering them to secrete interleukin-10 (IL-10). We show that IL-10 CAR T cells preserve intact mitochondrial structure and function in the tumor microenvironment and increase oxidative phosphorylation in a mitochondrial pyruvate carrier-dependent manner. IL-10 secretion promoted proliferation and effector function of CAR T cells, leading to complete regression of established solid tumors and metastatic cancers across several cancer types in syngeneic and xenograft mouse models, including colon cancer, breast cancer, melanoma and pancreatic cancer. IL-10 CAR T cells also induced stem cell-like memory responses in lymphoid organs that imparted durable protection against tumor rechallenge. Our results establish a generalizable approach to counter CAR T cell dysfunction through metabolic armoring, leading to solid tumor eradication and long-lasting immune protection. CAR T cells engineered to express IL-10 eradicate solid tumors and metastases.
引用
收藏
页码:1693 / 1704
页数:36
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