Summary: Blocking the CD161 pathway restores T-cell anti-tumor activity against gliomas and extends survival in preclinical brain cancer models.
Source: Dana-Farber Cancer Institute
Researchers report a promising new immunotherapy target for malignant brain tumors: the inhibitory receptor CD161 on tumor-infiltrating T cells. The findings, published in the journal Cell, come from laboratory and animal studies and do not yet translate into a clinical treatment for patients.
Investigators from Dana-Farber Cancer Institute, Massachusetts General Hospital, and the Broad Institute of MIT and Harvard identified CD161 as a molecule that dampens the ability of T cells to kill tumor cells in diffuse gliomas, including glioblastoma—the most aggressive and typically incurable form of brain cancer. CD161 is encoded by the KLRB1 gene and acts as an inhibitory receptor: when it binds its ligand CLEC2D, present on tumor cells and certain immunosuppressive myeloid cells in the tumor microenvironment, T-cell anti-tumor activity is reduced.
To test whether blocking CD161 could restore T-cell function, the team disabled the pathway in two ways. First, they used CRISPR/Cas9 gene editing to knock out KLRB1 in T cells. Second, they used blocking antibodies to interfere with the CD161–CLEC2D interaction. Both approaches enhanced T-cell killing of glioma cells in vitro, and in rodent models implanted with patient-derived glioma spheres, CD161-deficient T cells slowed tumor growth and significantly improved survival.
A key challenge in cancer immunotherapy is T-cell exhaustion — a progressive loss of the cells’ ability to kill cancer. The researchers observed that blocking the CD161 pathway reduced features of exhaustion in tumor-infiltrating T cells, suggesting the approach not only unleashes cytotoxic function but may also preserve T-cell durability within the immunosuppressive tumor microenvironment.
The team further noted that CD161 expression was more common than that of PD-1 among T cells in gliomas. Immune checkpoint inhibitors targeting PD-1 have had limited success in glioblastoma clinical trials; because a larger fraction of glioma-infiltrating T cells express CD161, it may represent a more relevant target in these tumors. CD161 is expressed on both CD8 and CD4 T-cell subsets, broadening its potential impact.
To map the molecular programs of glioma-infiltrating T cells, researchers performed single-cell RNA sequencing (single-cell RNA-seq) on T cells isolated from fresh tumor samples of 31 patients. This single-cell atlas revealed subsets of T cells that co-express cytotoxic gene programs and multiple natural killer (NK) cell receptors. Among these, KLRB1 emerged as a candidate inhibitory receptor associated with clonally expanded T cells in the tumor. Functional experiments confirmed that genetic inactivation of KLRB1 or antibody-mediated blockade of CD161 increased T-cell-mediated tumor cell killing in vitro and improved anti-tumor activity in vivo.
Beyond gliomas, the investigators found that KLRB1 and its associated transcriptional program are present in substantial T-cell populations across several major human cancers, including melanoma, lung, colon, and liver cancers. This suggests that targeting the CD161–CLEC2D axis could have broader relevance for cancer immunotherapy beyond brain tumors.
Animal testing employed two independent models in which human patient-derived gliomaspheres were implanted into rodents, producing invasive brain tumors. The research team infused T cells lacking KLRB1 into the cerebrospinal fluid of affected animals and compared outcomes with animals receiving unedited T cells. Animals treated with KLRB1-deficient T cells showed slower tumor progression and a clear survival advantage in both models.
The study was supported by the Ben and Catherine Ivy Foundation, the Bridge project, and several National Institutes of Health grants (including R01 CA238039, P01 CA236749, and R37CA245523). The authors caution that these results are preclinical: additional research is needed to evaluate safety and efficacy before any clinical trials in humans could be considered.
Several authors disclosed scientific advisory roles and research collaborations with biotechnology companies; these relationships are reported as part of the study’s disclosures.
About this brain cancer research news
Source: Dana-Farber Cancer Institute
Contact: Press Office – Dana-Farber Cancer Institute
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Original Research: Closed access. “Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis” by Nathan D. Mathewson et al., Cell.
Abstract
Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis
Highlights
- • Single-cell sequencing maps gene expression and clonal characteristics of glioma-infiltrating T cells.
- • Cytotoxic T cells express multiple NK cell receptors alongside effector programs.
- • The NK receptor CD161 (encoded by KLRB1) inhibits T-cell killing of glioma cells.
- • Tumor cells and immunosuppressive myeloid cells express the CLEC2D ligand that engages CD161.
Summary
T cells are central to cancer immunotherapy, yet their gene expression programs within diffuse gliomas have been poorly characterized. Using single-cell RNA sequencing of tumor-infiltrating T cells from 31 patients with IDH wild-type glioblastoma and IDH-mutant glioma, the study defines transcriptional and clonal landscapes and identifies effectors of anti-tumor immunity. Subsets of T cells co-express cytotoxic programs with several natural killer (NK) cell genes, including KLRB1 (CD161). Functional experiments show that genetic inactivation of KLRB1 or antibody blockade of CD161 enhances T-cell-mediated killing of glioma cells in vitro and improves anti-tumor function in vivo. KLRB1 and its transcriptional program are also present in significant T-cell populations in other cancers, highlighting CD161 and related NK receptors as potential targets for future immunotherapy development.