Two gene targets strengthen CAR-T; p53 takes more than 50 shapes
A CRISPR screen inside tumours found two gene targets that strengthen CAR-T cells; separate p53 research revealed more than 50 transient forms of the protein.
Science··Midday
The gene screen moved inside the tumour
Researchers at Gladstone Institutes and UCSF ran a genome-scale CRISPR screen inside tumours to investigate why CAR-T cells lose effectiveness against solid cancers. CAR-T therapy modifies a patient's T cells to recognise cancer cells. It can produce strong results in blood cancers, but the physical and chemical environment of a solid tumour makes it difficult for the cells to enter and remain active. The Nature study screened nearly 20,000 genes. Its method recovered 5 to 10 million T cells from each tumour, allowing the team to observe their behaviour directly in that environment. Two targets stood out. Deleting P2RY8 increased the movement of T cells into tumours. Deleting GNAS helped sustain interferon-gamma production and reduced the cells' responsiveness to suppressive signals from the tumour. Those effects address separate obstacles: reaching the target tissue and preserving function after arrival. The finding is not yet a treatment. It provides two gene targets that show how CAR-T cells may be made more resilient in the hostile setting of a solid tumour.[1]
Two edits worked together at a low dose
The most striking result appeared in a lung-cancer model when P2RY8 and GNAS were deleted together. At a low CAR-T dose, two-thirds of the mice remained tumour-free, an outcome that control cells did not produce. The researchers did not stop with one tumour type. They also used melanoma, pancreatic, gastroesophageal and uterine cancer models, along with human T cells taken from patients with ovarian cancer and melanoma. Six months of safety monitoring showed no long-term toxicity. Even so, the work remains at the level of mice and cell models, and the team says more safety and efficacy testing is needed before clinical trials. That distinction matters because a tumour-free share in mice does not establish the same outcome in people. The concrete contribution is the combination of two complementary functions in the same CAR-T cell. Removing P2RY8 improves entry into the tumour, while removing GNAS supports continued activity in a suppressive environment. Their shared effect at a low dose offers an approach beyond simply increasing cell numbers: changing both access to the tumour and resilience after arrival. The next step is to establish whether those edits remain safe and durable in further preclinical testing before they can move toward people.[1]
p53 behaves as a collection of shapes
The second cancer development concerns the workings of a familiar protein rather than a new treatment target. Researchers at the Max Planck Society followed the disordered N-terminal region of the tumour suppressor p53 by combining molecular-dynamics simulations with high-resolution nuclear magnetic resonance at 1.2 gigahertz. According to the Nature Communications study, p53 forms more than 50 distinct three-dimensional shapes despite lacking a fixed architecture. Those structures change across timescales from picoseconds to microseconds, spanning seven orders of magnitude. The forms are transient, yet stable enough to offer different surfaces as the protein encounters partners. Conventional methods could not detect the short-lived structures, so their variety had been missed in earlier experiments. The researchers suggest that this moving repertoire may help explain how p53 interacts with many different protein partners. The CAR-T study adjusts an immune cell through two gene deletions, while the p53 study reveals that one protein already behaves like a constantly shifting system. One makes visible the resilience of an immune cell attacking cancer; the other exposes the molecular flexibility of one of the cell's most important tumour suppressors. Both developments shift attention from a static target toward behaviour that changes inside a demanding biological environment.[2]
