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IL-10-expressing CAR T cells resist dysfunction and mediate durable clearance of solid tumors and metastases.
Zhao, Yang; Chen, Jiangqing; Andreatta, Massimo; Feng, Bing; Xie, Yu-Qing; Wenes, Mathias; Wang, Yi; Gao, Min; Hu, Xiaomeng; Romero, Pedro; Carmona, Santiago; Sun, Jie; Guo, Yugang; Tang, Li.
Afiliação
  • Zhao Y; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Chen J; Institute of Materials Science & Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Andreatta M; Department of Cell Biology and Bone Marrow Transplantation Center of the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, China.
  • Feng B; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
  • Xie YQ; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Wenes M; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Wang Y; Institute of Materials Science & Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Gao M; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Hu X; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
  • Romero P; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Carmona S; Institute of Materials Science & Engineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Sun J; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Guo Y; Institute of Bioengineering, École Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
  • Tang L; Department of Oncology, University of Lausanne, Lausanne, Switzerland.
Nat Biotechnol ; 2024 Jan 02.
Article em En | MEDLINE | ID: mdl-38168996
ABSTRACT
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.

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Base de dados: MEDLINE Idioma: En Ano de publicação: 2024 Tipo de documento: Article