Nature https://doi.org/10.1038/s41586-018-0499-y (2018)
The blood–brain barrier (BBB) forms a formidable vascular hurdle. Tumor endothelium upregulates activated leukocyte cell adhesion molecule (ALCAM), which engages its counter-ligand CD6, expressed on activated T cells. However, tumor endothelium downregulates expression of the ICAM1 and VCAM1 adhesion molecules, thereby preventing sustained T cell adhesion and extravasation into brain tumors. In Nature, Samaha et al. engineer expression of synthetic CD6 molecules on cytolytic T cells to exploit the tumor-induced changes in brain endothelium to deliver tumor immunotherapies. Multimerization of the CD6 D3 exodomain, which recognizes ALCAM, increases the avidity of T cell binding to tumor endothelium but not to normal brain endothelium. Signaling via the CD6 endodomain elicits additional cytoskeletal changes in T cells to facilitate their extravasation into tumor tissue. Engineered T cells expressing tumor-specific chimeric antigen receptors (CAR T cells) and engineered CD6 molecules exhibit better control of glioblastoma than do control T cells in mouse models. These findings point to therapeutic strategies for attacking brain tumors.
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17 April 2019
Editor’s Note: The editors of Nature Immunology wish to alert readers that the conclusions of the Nature article “A homing system targets therapeutic T cells to brain cancer” by Samaha et al., on which this Research Highlight was based, have been challenged after we went to press. Accordingly, the observations discussed here should be interpreted with caution until these challenges have been thoroughly investigated.
Editor’s Note: The editors of Nature Immunology wish to alert readers that the Nature article “A homing system targets therapeutic T cells to brain cancer” by Samaha et al., on which this Research Highlight was based, was HYPERLINK “https://www.nature.com/articles/s41586-019-0967-z” retracted on 20 February 2019.
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Dempsey, L.A. Missile guidance for brain tumors. Nat Immunol 19, 1148 (2018). https://doi.org/10.1038/s41590-018-0245-5
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DOI: https://doi.org/10.1038/s41590-018-0245-5
