Abstract
In glioma, tumor-infiltrating cytotoxic T cells expressed the inhibitory NK-cell receptor CD161.
Major Finding: In glioma, tumor-infiltrating cytotoxic T cells expressed the inhibitory NK-cell receptor CD161.
Concept: Blocking the inhibitory CD161–CLEC2D pathway activated T cell–mediated killing of glioma cells.
Impact: This work identifies the CD161 receptor as a novel immunotherapy target in glioma and other cancers.
Immune checkpoint inhibitors have so far shown a lack of clinical efficacy in patients with glioma, highlighting the need to better understand glioma-infiltrating T cells. To characterize the expression and function of infiltrating T-cell populations, Mathewson, Ashenberg, Tirosh, Gritsch, Perez, Marx, and colleagues analyzed tumor-infiltrating T cells from 31 patients with IDH–wild-type glioblastoma (GBM; n = 16) or IDH-mutant glioma (n = 15). T cells were profiled via single-cell RNA sequencing, revealing CD4+ and CD8+ T-cell populations that clustered into several subsets, including some that expressed an IFN signature, an effector memory signature, or a stress signature. Notably, a subcluster of CD8+ T cells co-expressed cytotoxicity genes and natural killer (NK)–cell genes. To investigate whether increased NK-cell gene expression was linked to cytotoxic T-cell function, T cells were scored for defined cytotoxicity and NK-cell signatures, revealing that higher cytotoxicity scores correlated with higher NK-cell signatures. CD8+ T cells with high cytotoxicity consistently expressed genes encoding various NK-cell receptors, such as KLRB1, encoding the NK-cell receptor CD161. Focusing on tumor-reactive T cells, further analysis found that clonally expanded CD8+ T cells had higher expression of both cytotoxicity genes and NK-cell receptor–encoding genes, including KLRB1. CD161 has previously been shown to inhibit NK-cell cytotoxicity when bound to the ligand CLEC2D. Expression of CLEC2D was confirmed in glioma cells, providing evidence for activity of the inhibitory CD161–CLEC2D pathway in glioma. Inhibiting this pathway via CRISPR–Cas9-mediated mutagenesis of KLRB1 in human T-cell coculture assays and in humanized mouse models of GBM enhanced T cell–mediated cytotoxicity in addition to slowing tumor growth and extending survival. Transcriptomic analysis detected the KLBR1 transcriptional program in tumor-infiltrating cells of other human cancer types, defining a pan-cancer KLBR1 signature. In summary, this work generates a comprehensive single-cell T-cell atlas of tumor-infiltrating T cells in glioma and identifies an inhibitory receptor–ligand pathway as a novel immunotherapy target to enhance the antitumor response in glioma and possibly other cancers.
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