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CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy

Cancer Gene Therapy (2024)Cite this article

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Abstract

While CAR-T and tgTCR-T therapies have exhibited noteworthy and promising outcomes in hematologic and solid tumors respectively, a set of distinct challenges remains. Consequently, the quest for novel strategies has become imperative to safeguard and more effectively release the full functions of engineered T cells. These factors are intricately linked to the success of adoptive cell therapy. Recently, CRISPR-based technologies have emerged as a major breakthrough for maintaining T cell functions. These technologies have allowed the discovery of T cells’ negative regulators such as specific cell-surface receptors, cell-signaling proteins, and transcription factors that are involved in the development or maintenance of T cell dysfunction. By employing a CRISPR-genic invalidation approach to target these negative regulators, it has become possible to prevent the emergence of hypofunctional T cells. This review revisits the establishment of the dysfunctional profile of T cells before delving into a comprehensive summary of recent CRISPR-gene invalidations, with each invalidation contributing to the enhancement of engineered T cells’ antitumor capacities. The narrative unfolds as we explore how these advancements were discovered and identified, marking a significant advancement in the pursuit of superior adoptive cell therapy.

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Fig. 1: Drivers of T cell dysfunction.
Fig. 2: T cells’ loss of function.
Fig. 3: CRISPR-Cas principle.
Fig. 4

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Acknowledgements

The figures were created with BioRender.com.

Funding

This work was supported by Ligue contre le cancer N°2022-0047.

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  1. Université de Franche-Comté, EFS, INSERM, UMR RIGHT, F-25000, Besançon, France

    Valentine De Castro, Jeanne Galaine, Romain Loyon & Yann Godet

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  1. Valentine De Castro
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  2. Jeanne Galaine
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  3. Romain Loyon
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  4. Yann Godet
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The authors reviewed the literature cited and wrote the manuscript. They all read and approved the final manuscript.

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Correspondence to Yann Godet.

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De Castro, V., Galaine, J., Loyon, R. et al. CRISPR-Cas gene knockouts to optimize engineered T cells for cancer immunotherapy. Cancer Gene Ther (2024). https://doi.org/10.1038/s41417-024-00771-x

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