Inosine induces stemness features in CAR-T cells and enhances potency,Cancer Cell

当前位置： X-MOL 学术 › Cancer Cell › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Inosine induces stemness features in CAR-T cells and enhances potency
Cancer Cell ( IF 48.8 ) Pub Date : 2024-01-25 , DOI: 10.1016/j.ccell.2024.01.002
Dorota D Klysz ₁ , Carley Fowler ₁ , Meena Malipatlolla ₁ , Lucille Stuani ₂ , Katherine A Freitas ₁ , Yiyun Chen ₁ , Stefanie Meier ₃ , Bence Daniel ₄ , Katalin Sandor ₅ , Peng Xu ₁ , Jing Huang ₁ , Louai Labanieh ₁ , Vimal Keerthi ₁ , Amaury Leruste ₁ , Malek Bashti ₁ , Janette Mata-Alcazar ₁ , Nikolaos Gkitsas ₁ , Justin A Guerrero ₁ , Chris Fisher ₁ , Sunny Patel ₁ , Kyle Asano ₁ , Shabnum Patel ₁ , Kara L Davis ₆ , Ansuman T Satpathy ₇ , Steven A Feldman ₁ , Elena Sotillo ₁ , Crystal L Mackall ₈

Affiliation

Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA.
Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Gladstone-UCSF Institute of Genomic Immunology, San Francisco, CA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA; Center for Personal Dynamic Regulomes, Stanford University, Stanford, CA, USA.
Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA.
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pathology, Stanford University School of Medicine, Stanford, CA, USA.
Center for Cancer Cell Therapy, Stanford Cancer Institute, Stanford University School of Medicine, Stanford, CA, USA; Parker Institute for Cancer Immunotherapy, San Francisco, CA, USA; Department of Pediatrics, Division of Pediatric Hematology, Oncology, Stem Cell Transplantation and Regenerative Medicine, Stanford University School of Medicine, Stanford, CA, USA; Department of Medicine, Division of Bone Marrow Transplantation and Cell Therapy, Stanford University School of Medicine, Stanford, CA, USA.

Adenosine (Ado) mediates immune suppression in the tumor microenvironment and exhausted CD8 CAR-T cells express CD39 and CD73, which mediate proximal steps in Ado generation. Here, we sought to enhance CAR-T cell potency by knocking out CD39, CD73, or adenosine receptor 2a (A2aR) but observed only modest effects. In contrast, overexpression of Ado deaminase (ADA-OE), which metabolizes Ado to inosine (INO), induced stemness and enhanced CAR-T functionality. Similarly, CAR-T cell exposure to INO augmented function and induced features of stemness. INO induced profound metabolic reprogramming, diminishing glycolysis, increasing mitochondrial and glycolytic capacity, glutaminolysis and polyamine synthesis, and reprogrammed the epigenome toward greater stemness. Clinical scale manufacturing using INO generated enhanced potency CAR-T cell products meeting criteria for clinical dosing. These results identify INO as a potent modulator of CAR-T cell metabolism and epigenetic stemness programming and deliver an enhanced potency platform for cell manufacturing.

中文翻译：

肌苷诱导 CAR-T 细胞干性特征并增强效力

腺苷 (Ado) 介导肿瘤微环境中的免疫抑制，并且耗尽的 CD8 CAR-T 细胞表达 CD39 和 CD73，从而介导 Ado 生成的近端步骤。在这里，我们试图通过敲除 CD39、CD73 或腺苷受体 2a (A2aR) 来增强 CAR-T 细胞效力，但仅观察到适度的效果。相比之下，Ado 脱氨酶 (ADA-OE) 的过度表达（将 Ado 代谢为肌苷 (INO)）会诱导干性并增强 CAR-T 功能。同样，CAR-T 细胞暴露于 INO 会增强功能并诱导干性特征。 INO 诱导深刻的代谢重编程，减少糖酵解，增加线粒体和糖酵解能力，谷氨酰胺分解和多胺合成，并将表观基因组重新编程为更大的干性。使用 INO 进行临床规模生产，产生符合临床剂量标准的增强效力 CAR-T 细胞产品。这些结果表明 INO 是 CAR-T 细胞代谢和表观遗传干性编程的有效调节剂，并为细胞制造提供增强的效力平台。

更新日期：2024-01-25

点击分享查看原文

点击收藏

公开下载

阅读更多本刊新发论文本刊介绍/投稿指南