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Fate induction in CD8 CAR T cells through asymmetric cell division
Casey S Lee1,2, Sisi Chen1,2, Corbett T Berry1,2
1Department of Dermatology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Nature
|August 28, 2024
Summary
Asymmetric cell division in chimeric antigen receptor T cells (CARTs) dictates distinct cell fates. This discovery reveals how CARTs differentiate, offering a new framework for enhancing cancer therapy efficacy.
Area of Science:
- Immunology
- Cell Biology
- Cancer Therapy
Background:
- Early expansion and long-term persistence of chimeric antigen receptor T cells (CARTs) are crucial for therapeutic efficacy.
- Mechanisms governing effector versus memory CART differentiation and the role of asymmetric cell division in human CARTs are not fully understood.
Purpose of the Study:
- To investigate the mechanisms of CART differentiation, specifically focusing on asymmetric cell division and its impact on cell fate.
- To elucidate how CARTs achieve divergent fates, leading to effector or memory cell populations.
Main Methods:
- Utilized target-induced proximity labeling to isolate first-division proximal-daughter and distal-daughter CD8 CARTs.
- Analyzed surface proteome and transcriptome of daughter cells to identify differences in cell fate determinants.
- Assessed metabolic profiles, transcriptional trajectories, and transcription factor usage in daughter cells.
- Investigated the role of IKZF1 in distal-daughter CART function and persistence.
Main Results:
- Asymmetric cell division in CARTs leads to daughter cells with distinct surface proteomes and transcriptomes, resulting in divergent fates.
- Proximal daughters retain target-engaged CARs and resemble activated CARTs, while distal daughters enrich for endogenous T cell receptor and CD8, resembling resting CARTs.
- Distal daughters, despite a memory-precursor phenotype, exhibit transient potent cytolytic activity, indicating an effector-like state.
- Transcriptional asymmetry, driven by transcript partitioning and RNA velocity, results in opposing differentiation trajectories.
- Disruption of IKZF1 diminishes long-term in vivo persistence and function of distal-daughter CARTs.
Conclusions:
- Asymmetric cell division is a fundamental mechanism governing CART differentiation and fate determination.
- Understanding these mechanisms provides a framework for improving CART therapy by potentially manipulating cell division to enhance therapeutic outcomes.
- The study uncovers an effector-like state in distal-daughter CARTs, challenging traditional views of memory cell development.
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