Nature study identifies P2RY8 and GNAS T-cell targets in solid tumours
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A genome-wide in vivo CRISPR screen in human T cells identifies P2RY8–Gα13 as a negative regulator of tumour infiltration and GNAS as a key driver of T-cell dysfunction in solid tumours, according to a paper published in Nature. Knockout of GNAS makes T cells resistant to multiple suppressive cues and improves efficacy across diverse solid tumour models in CAR and TCR systems. Combinatorial knockout of P2RY8 and GNAS further enhances tumour control, while Gαs acts as a convergent node downstream of multiple GPCRs.
In Vivo CRISPR Platform
The Nature paper describes an in vivo model that efficiently recovers human T cells from solid tumours, enabling genome-wide CRISPR screens with few mice. Tumour-infiltrating T cells from this model show hallmarks of dysfunction compared with splenic T cells. The study performed two genome-wide CRISPR knockout screens to identify regulators of intratumoural T cell abundance and effector function. RNA sequencing raw data are deposited in Gene Expression Omnibus under accession GSE330227.
P2RY8–Gα13 Infiltration Axis
The abundance screen in the Nature study identified the P2RY8–Gα13 GPCR signalling axis as a negative regulator of T cell tumour infiltration. The axis was not revealed by earlier in vitro screens, which missed many regulators of T cell performance in solid tumours. P2RY8 and Gα13 are the named components of this GPCR pathway. The finding provides one of two orthogonal targets from the complementary screens.
GNAS and Combination Editing
The effector function screen in the Nature paper identified GNAS as a key driver of T cell dysfunction in tumours. Its product, Gαs, acts as a convergent node downstream of multiple GPCRs sensing distinct suppressive ligands. Knockout of GNAS rendered T cells resistant to multiple suppressive cues and significantly improved efficacy across CAR and TCR solid tumour models. Combinatorial knockout of P2RY8 and GNAS further enhanced tumour control, showing orthogonal targets can be edited together.
What's Next
The authors describe the platform as adaptable for systematic discovery of genetic strategies to improve solid tumour T cell therapies, but they do not specify a timeline for clinical translation. It remains unclear whether the P2RY8 and GNAS edits will produce the same effects in human trials.
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Nature study identifies P2RY8 and GNAS T-cell targets in solid tumours
