CRISPR screens of tumor-infiltrating NK cells identify genetic checkpoints for CAR-NK therapy

We use a CRISPR screening platform based on adeno-associated virus and the Sleeping Beauty transposon (AAV-SB-CRISPR) to perform in vivo CRISPR screens in primary natural killer (NK) cells across four different tumor models, and identify calcium homeostasis modulator family member 2 (CALHM2) as an NK cellular checkpoint protein.

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Fig. 1: AAV-SB-CRISPR screens and single-cell RNA sequencing of tumor-infiltrating NK cells jointly identify CALHM2 as an NK cellular checkpoint.

References

Marin, D. et al. Safety, efficacy and determinants of response of allogeneic CD19-specific CAR-NK cells in CD19+ B cell tumors: a phase 1/2 trial. Nat. Med. 30, 772–784 (2024). A recent clinical trial demonstrating the robust efficacy and superior safety of CAR-NK.

Vivier, E. et al. Natural killer cell therapies. Nature 626, 727–736 (2024). Comprehensive review discussing the current status of NK therapy.

Dong, M. B. Systematic immunotherapy target discovery using genome-scale in vivo CRISPR screens in CD8 T cells. Cell 178, 1189–1204 (2019). This paper reports an early in vivo CRISPR screens in primary T cells.

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Ye, L. et al. In vivo CRISPR screening in CD8 T cells with AAV-Sleeping Beauty hybrid vectors identifies membrane targets for improving immunotherapy for glioblastoma. Nat. Biotechnol. 37, 1302–1313 (2019). This paper demonstrates the application of an AAV-SB-CRISPR system in T cells.

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This is a summary of: Peng, L. et al. In vivo AAV–SB-CRISPR screens of tumor-infiltrating primary NK cells identify genetic checkpoints of CAR-NK therapy. Nat. Biotechnol. https://doi.org/10.1038/s41587-024-02282-4 (2024).

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CRISPR screens of tumor-infiltrating NK cells identify genetic checkpoints for CAR-NK therapy.
Nat Biotechnol (2024). https://doi.org/10.1038/s41587-024-02319-8

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Published: 25 June 2024

DOI: https://doi.org/10.1038/s41587-024-02319-8

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