SUV39H1 Ablation Enhances Long-term CAR T Function in Solid Tumors

Area of Science:

• Immunology
• Epigenetics
• Cancer Therapy

Background:

• Adoptive T-cell therapies, including chimeric antigen receptor (CAR) T cells, face challenges with limited T-cell expansion and persistence in cancer patients.
• Memory-prone 41BB-based CAR T cells still exhibit suboptimal long-term efficacy, hindering therapeutic responses, particularly in solid tumors.

Purpose of the Study:

• To investigate the potential of epigenetic manipulation of the histone 3 lysine 9 trimethylation (H3K9me3) pathway to enhance CAR T-cell stem/memory differentiation and persistence.
• To determine if inactivating the H3K9 trimethyltransferase SUV39H1 can improve the long-term functional persistence of BBz-CAR T cells.

Main Methods:

• Inactivation of the SUV39H1 gene in BBz-CAR T cells.
• In vivo studies using mouse models with lung and disseminated solid tumors.
• Single-cell transcriptomic (scRNA-seq) and single-cell assay for transposase accessible chromatin (scATAC-seq) analyses of tumor-infiltrating CAR T cells.

Main Results:

• Inactivation of SUV39H1 significantly enhanced the long-term persistence of BBz-CAR T cells in mice.
• Treated mice showed protection against tumor relapses and rechallenges for several months post-infusion.
• Single-cell analyses revealed reprogramming of CAR T cells into self-renewing, stem-like populations with reduced expression of dysfunction genes.

Conclusions:

• Epigenetic modification of H3K9 methylation by targeting SUV39H1 optimizes the long-term functional persistence of BBz-CAR T cells.
• This approach limits tumor relapses and provides enhanced protection against tumor rechallenges.
• Targeting SUV39H1 represents a promising and safe strategy to improve adoptive cell therapies for solid tumors.