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SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors.
López-Cobo, Sheila; Fuentealba, Jaime R; Gueguen, Paul; Bonté, Pierre-Emmanuel; Tsalkitzi, Kyriaki; Chacón, Irena; Glauzy, Salomé; Bohineust, Armelle; Biquand, Ariane; Silva, Lisseth; Gouveia, Zelia; Goudot, Christel; Perez, Franck; Saitakis, Michael; Amigorena, Sebastian.
Afiliação
  • López-Cobo S; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
  • Fuentealba JR; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
  • Gueguen P; Department of Oncology, UNIL CHUV and Ludwig Institute for Cancer Research Lausanne, University of Lausanne, Lausanne, Switzerland.
  • Bonté PE; Agora Cancer Research Center, Lausanne, Switzerland.
  • Tsalkitzi K; Swiss Institute of Bioinformatics, Lausanne, Switzerland.
  • Chacón I; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
  • Glauzy S; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
  • Bohineust A; Mnemo Therapeutics, Paris, France.
  • Biquand A; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
  • Silva L; Institut Curie, PSL Research University, Sorbonne Université, CNRS, UMR 144, Paris, France.
  • Gouveia Z; Mnemo Therapeutics, Paris, France.
  • Goudot C; Mnemo Therapeutics, Paris, France.
  • Perez F; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
  • Saitakis M; Institut Curie, PSL Research University, Sorbonne Université, CNRS, UMR 144, Paris, France.
  • Amigorena S; Institut Curie, PSL University, Inserm U932, Immunity and Cancer, Paris, France.
Cancer Discov ; 14(1): 120-141, 2024 01 12.
Article em En | MEDLINE | ID: mdl-37934001
Failure of adoptive T-cell therapies in patients with cancer is linked to limited T-cell expansion and persistence, even in memory-prone 41BB-(BBz)-based chimeric antigen receptor (CAR) T cells. We show here that BBz-CAR T-cell stem/memory differentiation and persistence can be enhanced through epigenetic manipulation of the histone 3 lysine 9 trimethylation (H3K9me3) pathway. Inactivation of the H3K9 trimethyltransferase SUV39H1 enhances BBz-CAR T cell long-term persistence, protecting mice against tumor relapses and rechallenges in lung and disseminated solid tumor models up to several months after CAR T-cell infusion. Single-cell transcriptomic (single-cell RNA sequencing) and chromatin opening (single-cell assay for transposase accessible chromatin) analyses of tumor-infiltrating CAR T cells show early reprogramming into self-renewing, stemlike populations with decreased expression of dysfunction genes in all T-cell subpopulations. Therefore, epigenetic manipulation of H3K9 methylation by SUV39H1 optimizes the long-term functional persistence of BBz-CAR T cells, limiting relapses, and providing protection against tumor rechallenges. SIGNIFICANCE: Limited CAR T-cell expansion and persistence hinders therapeutic responses in solid cancer patients. We show that targeting SUV39H1 histone methyltransferase enhances 41BB-based CAR T-cell long-term protection against tumor relapses and rechallenges by increasing stemness/memory differentiation. This opens a safe path to enhancing adoptive cell therapies for solid tumors. See related article by Jain et al., p. 142. This article is featured in Selected Articles from This Issue, p. 5.
Assuntos

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Antígenos Quiméricos / Neoplasias Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Receptores de Antígenos Quiméricos / Neoplasias Limite: Animals / Humans Idioma: En Ano de publicação: 2024 Tipo de documento: Article