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Brain tumor T cells inhibited by their natural KLR(B1) instinct

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Science Immunology  02 Apr 2021:
Vol. 6, Issue 58, eabi7302
DOI: 10.1126/sciimmunol.abi7302

Abstract

Charting the gene-expression landscape of glioma-infiltrating T cells demonstrates that these T cells can express NK cell receptors, which inhibit the killing of glioma cells.

Immunotherapy has the potential to overcome treatment limitations in the deadliest forms of brain cancer. However, despite continuous efforts, the prognosis for patients diagnosed with diffuse glioma, the most common type of primary brain tumor, remains poor. Isocitrate dehydrogenase (IDH) mutant glioma (IDH-G) and IDH-wild type glioblastoma (GBM), the two major classes of diffuse gliomas, are characterized by their rapid growth rate and resistance to treatment. The current standard of care for newly diagnosed patients consists of maximal surgical resection followed by concurrent radiation and chemotherapy. The molecular heterogeneity of diffuse gliomas has resulted in the failure of targeted treatments, and the immunosuppressive microenvironment created by these tumors has limited the efficacy of immunotherapeutic trials. Therefore, understanding the immune landscape of diffuse gliomas is critical for improving the efficacy of immunotherapy in treatment-resistant malignancies.

Using single-cell RNA sequencing, Mathewson et al. characterized the gene-expression programs of tumor-infiltrating T cells in IDH-G and GBM. They found co-expression of cytotoxicity programs and NK cell receptors in clonally expanded tumor-infiltrating CD8 T cells with diverse T cell receptor repertoires. The authors chose the KLRB1 gene for further study, which encodes the NK receptor CD161 (CLEC2D, the ligand for CD161, is expressed by malignant cells). Characterization of the CD161-CLEC2D pathway in diffuse glioma in vitro demonstrated the inhibitory effect of CD161 activation on T cell function, and in vivo experiments using humanized mouse models showed increased survival and anti-tumor activity in mice that received transferred T cells with inactivated KLRB1. The presence of KLRB1 expression in other types of cancer suggests that the treatment potential of the blockade of this pathway extends beyond diffuse gliomas.

This study identified the CD161-CLEC2D pathway as a potential new target for immunotherapy in diffuse gliomas and highlighted the importance of receptors typically expressed by NK cells in tumor-infiltrating T cells. Although the intrinsic and adaptive resistance mechanisms of malignant cells in IDH-G and GBM have resulted in the failure of immunotherapeutic approaches that have been successful with other types of cancer, the identification of specific targetable pathways is important for the development of more effective therapies.

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