期刊
BLOOD
卷 139, 期 14, 页码 2156-2172出版社
AMER SOC HEMATOLOGY
DOI: 10.1182/blood.2021012714
关键词
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类别
资金
- AMED [JP20ae0201013, JP21bm0704066]
- JSPS KAKENHI [20H03543, 19K22552]
- Takara Bio, Inc
- Aichi Cancer Center Joint Research Project on Priority Areas
- Ichiro Kanehara Foundation
- Yasuda Medical Foundation
- Senri Life Science Foundation
- Princess Takamatsunomiya Cancer Research Foundation
- Takeda Science Foundation
- Senshin Medical Research Foundation
- Uehara Memorial Foundation
- Japan Leukemia Research Fund
- Japanese Society of Hematology Research Grant
- Astellas Foundation for Research on Metabolic Disorders
- Mochida Memorial Foundation for Medical and Pharmaceutical Research
- SGH Foundation
- Tokyo Biochemical Research Foundation
- Nippon Shinyaku Research Grant
- Bristol-Myers Squibb Research Grant
- KAKENHI [19K09297, 20K22793, 19H03528]
- Grants-in-Aid for Scientific Research [19H03528, 19K22552, 19K09297, 20K22793, 20H03543] Funding Source: KAKEN
This study identifies PRDM1 as a key epigenetic gene associated with terminal T-cell differentiation. Knockout of PRDM1 promotes early memory phenotype and polyfunctional cytokine secretion in T cells, enhancing T-cell persistence and therapeutic efficacy in multiple tumor models. Targeting PRDM1 enables the generation of superior antitumor T cells applicable to a wide range of adoptive cancer immunotherapies.
Adoptive cancer immunotherapy can induce objective clinical efficacy in patients with advanced cancer; however, a sustained response is achieved in a minority of cases. The persistence of infused T cells is an essential determinant of a durable therapeutic response. Antitumor T cells undergo a genome-wide remodeling of the epigenetic architecture upon repeated antigen encounters, which inevitably induces progressive T-cell differentiation and the loss of longevity. In this study, we identified PR domain zinc finger protein 1 (PRDM1) ie, Blimp-1, as a key epigenetic gene associated with terminal T-cell differentiation. The genetic knockout of PRDM1 by clustered regularly interspaced short palindromic repeats (CRISPR)/CRISPR-associated protein 9 (Cas9) supported the maintenance of an early memory phenotype and polyfunctional cytokine secretion in repeatedly stimulated chimeric antigen receptor (CAR)-engineered T cells. PRDM1 disruption promoted the expansion of less differentiated memory CAR-T cells in vivo, which enhanced T-cell persistence and improved therapeutic efficacy in multiple tumor models. Mechanistically, PRDM1-ablated T cells displayed enhanced chromatin accessibility of the genes that regulate memory formation, thereby leading to the acquisition of gene expression profiles representative of early memory T cells. PRDM1 knockout also facilitated maintaining an early memory phenotype and cytokine polyfunctionality in T-cell receptor-engineered T cells as well as tumor-infiltrating lymphocytes. In other words, targeting PRDM1 enabled the generation of superior antitumor T cells, which is potentially applicable to a wide range of adoptive cancer immunotherapies.
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