Technique turns immune cells into cancer-seeking bloodhounds

A Stanford Medicine study published in Nature Immunology reports a method that equips immune cells with metabolite-sensing receptors, which increased tumor infiltration and improved control of human breast and ovarian tumors in mice.

A Stanford Medicine team reports a laboratory technique that equips immune cells with surface receptors that sense molecules released by tumors. The study, published March 23 in Nature Immunology, tested the approach in mice bearing human breast and ovarian cancers. The engineered receptors belong to a class of G-protein coupled receptors the authors call tumor-homing GPRs, or thGPRs. The work addresses a known challenge in cell therapy for solid tumors by improving immune cell migration into tumor tissue. Key findings: - Researchers screened 256 candidate genes using CRISPR activation in human NK cells and identified six GPCRs (thGPRs) that consistently increased tumor infiltration. - The identified thGPRs respond to chemoattracting metabolites such as phospholipids, fatty acids and oxidized cholesterol produced by cancer cells. - Engineering NK cells and T cells, including CAR-modified cells, to express GPR183 boosted migration toward tumors and improved tumor control and survival in mice with human breast and ovarian cancers. - This strategy differs from standard CAR-T approaches by sensing diffusible tumor metabolites rather than proteins anchored to cancer-cell surfaces. - The authors report plans to advance GPR183-engineered cells toward clinical testing and to evaluate other thGPRs for therapeutic potential. Summary: The study indicates that metabolite-sensing receptors can guide cancer-killing immune cells into solid tumors and improve tumor control in preclinical models. Researchers are moving toward clinical testing of GPR183-engineered cells and continue to study other thGPRs. The extent of clinical benefit in humans remains to be established.