Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

Mathewson, Nathan D.; Ashenberg, Orr; Tirosh, Itay; Gritsch, Simon; Perez, Elizabeth M.; Marx, Sascha; Jerby‐Arnon, Livnat; Chanoch-Myers, Rony; Hara, Toshiro; Richman, Alyssa; Ito, Yoshinaga; Pyrdol, Jason W.; Friedrich, Mirco; Schumann, Kathrin; Poitras, Michael J.; Gokhale, Prafulla C.; Castro, L Nicolas Gonzalez; Shore, Marni E.; Hebert, Christine; Shaw, Brian; Cahill, Heather L.; Drummond, Matthew; Zhang, Wubing; Olawoyin, Olamide; Wakimoto, Hiroaki; Rozenblatt-Rosen, Orit; Brastianos, Priscilla K.; Liu, X. Shirley; Jones, Pamela S.; Cahill, Daniel P.; Frosch, Matthew P.; Louis, David N.; Freeman, Gordon J.; Ligon, Keith L.; Marson, Alexander; Chiocca, E. Antonio; Reardon, David A.; Regev, Aviv; Suvà, Mario L.; Wucherpfennig, Kai W.

doi:10.1016/j.cell.2021.01.022

Cited by 277 publications

(276 citation statements)

References 66 publications

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“…For example, combining anti-PD-1 with anti-TIM-3 improved overall survival from 28% (anti-PD-1 alone) to 60% (dual therapy) in preclinical GL261 models, and this was further enhanced to 100% when combined as a triple therapy with stereotactic radiosurgery (SRS) ( 73 ). In addition to the PD-1 pathway, recent work has identified expression of the inhibitory receptor CD161 on intratumoral T cells in glioblastoma, and blockade of CD161 enhanced T cell anti-tumor activity both in vitro and in GL261 transplantable mouse models ( 74 ). Interestingly, CD161 is encoded by the NK cell gene, KLRB1 , highlighting NK cell receptors as potential targets for immunotherapy.…”

Section: Immune Privilege and The Central Nervous System: A Case For Immunotherapymentioning

confidence: 99%

Immunotherapy for Glioblastoma: Current Progress and Challenges

Quail

2021

Front. Immunol.

118

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Glioblastoma is a highly lethal brain cancer with a median survival rate of less than 15 months when treated with the current standard of care, which consists of surgery, radiotherapy and chemotherapy. With the recent success of immunotherapy in other aggressive cancers such as advanced melanoma and advanced non-small cell lung cancer, glioblastoma has been brought to the forefront of immunotherapy research. Resistance to therapy has been a major challenge across a multitude of experimental candidates and no immunotherapies have been approved for glioblastoma to-date. Intra- and inter-tumoral heterogeneity, an inherently immunosuppressive environment and tumor plasticity remain barriers to be overcome. Moreover, the unique tissue-specific interactions between the central nervous system and the peripheral immune system present an additional challenge for immune-based therapies. Nevertheless, there is sufficient evidence that these challenges may be overcome, and immunotherapy continues to be actively pursued in glioblastoma. Herein, we review the primary ongoing immunotherapy candidates for glioblastoma with a focus on immune checkpoint inhibitors, myeloid-targeted therapies, vaccines and chimeric antigen receptor (CAR) immunotherapies. We further provide insight on mechanisms of resistance and how our understanding of these mechanisms may pave the way for more effective immunotherapeutics against glioblastoma.

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Section: Immune Privilege and The Central Nervous System: A Case For Immunotherapymentioning

confidence: 99%

Immunotherapy for Glioblastoma: Current Progress and Challenges

Quail

2021

Front. Immunol.

118

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“…CD161, encoded by KLRB1, is newly reported as a candidate inhibitor of tumour-infiltrating T cells. Antibodymediated CD161 blockade enhances T cell-mediated killing of cancer cells in vitro and in vivo in a few tumour types (5,6). In this study, we evaluated the role of CD161 using TCGA pan-cancer.…”

Section: Discussionmentioning

confidence: 99%

“…A recent study using single-cell RNA sequencing of tumour-infiltrating T cells discovered that CD161 acts as a potential inhibitory receptor in liver cancer and glioma. C-Type lectin domain family 2 member D, the ligand of CD161, is expressed on the cell membranes of malignant tumour cells, forming a ligand-receptor pathway for immunotherapy (5,6). Previous research has proven that the expression of CD161 in lung cancer is associated with better clinical outcomes (7).…”

Section: Introductionmentioning

confidence: 99%

A Pan-Cancer Analysis of CD161, a Potential New Immune Checkpoint

Zhou

Liu

et al. 2021

Front. Immunol.

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BackgroundCD161, encoded by killer cell lectin-like receptor B1 gene, is a newly reported candidate inhibitor of tumour-infiltrating T cells. Antibody-mediated CD161 blockade enhances T cell-mediated killing of cancer cells in vitro and in vivo in several tumour types. We evaluated the role of CD161 using The Cancer Genome Atlas (TCGA) Pan-Cancer Data.MethodsCD161 expression was analysed using RNAseq data from TCGA and the Genotype-Tissue Expression (GTEx) database. HPA, GeneCards, and String database were used to explore the protein information of CD161. The prognostic value of CD161 was analysed using clinical survival data from the TCGA. Enrichment analysis of CD161 was conducted using the R package “clusterProfiler”. We downloaded the immune cell infiltration score of TCGA samples from published articles and online databases and performed a correlation analysis between immune cell infiltration levels and CD161 expression. We further assessed the association between CD161 and immune checkpoints, immune activating genes, immunosuppressive genes, chemokines, and chemokine receptors.FindingsCD161 was differentially expressed and predicted better survival status in most tumour types in TCGA. In addition, CD161 expression was significantly associated with immunoregulatory interactions between lymphoid and non-lymphoid cells. CD161 expression was closely correlated with T cell infiltration, immune checkpoints, immune activating genes, immunosuppressive genes, chemokines, and chemokine receptors.InterpretationOur results suggest that CD161 is a potential cancer biomarker. CD161 might synergize with other immune checkpoints to regulate the immune microenvironment, which could be applied in the development of new-targeted drugs for immunotherapy.FundingThis work was supported by the National Nature Science Foundation of China (grant numbers 81773008, 81672756, 81872399, 81972897), the Guangdong Province Universities and Colleges Pearl River Scholar Funded Scheme (2015), the Natural Science Foundation of Guangdong Province (grant number 2017A030311023), the Local Innovative and Research Teams Project of Guangdong Pearl River Talents Program: 2017BT01S131 and the Guangzhou Technology Project (grant number 201804010044), National Key R&D Program of China (Grant Nos. 2020YFC2006400), Key-Area Research and Development Program of Guangdong Province (2019B020227004).

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“…On the other hand, an increased understanding of the possible indicators of side effects of immunotherapies will lead to improved clinical care and make the application of immunotherapies far safer and well-tolerated for glioma patients. Despite formidable challenges, with the advent of single-cell transcriptomic analysis ( Wang et al, 2019 ; Gibellini et al, 2020 ; Mathewson et al, 2021 ), high parameter mass cytometry ( Hartmann et al, 2019 ; Wang et al, 2019 ; Gohil et al, 2021 ), and high-resolution Hyperion imaging technologies ( Carvajal-Hausdorf et al, 2019 ; Xie et al, 2020 ), the glioma immunotherapy field is undergoing unprecedented growth in the discovery of novel therapeutic targets and interventions, that we envisage will lead to effective novel treatments for this devastating brain cancer in the near future.…”

Section: Immunotherapy In Gliomamentioning

confidence: 99%

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

et al. 2021

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Gliomas are one of the most lethal types of cancers accounting for ∼80% of all central nervous system (CNS) primary malignancies. Among gliomas, glioblastomas (GBM) are the most aggressive, characterized by a median patient survival of fewer than 15 months. Recent molecular characterization studies uncovered the genetic signatures and methylation status of gliomas and correlate these with clinical prognosis. The most relevant molecular characteristics for the new glioma classification are IDH mutation, chromosome 1p/19q deletion, histone mutations, and other genetic parameters such as ATRX loss, TP53, and TERT mutations, as well as DNA methylation levels. Similar to other solid tumors, glioma progression is impacted by the complex interactions between the tumor cells and immune cells within the tumor microenvironment. The immune system’s response to cancer can impact the glioma’s survival, proliferation, and invasiveness. Salient characteristics of gliomas include enhanced vascularization, stimulation of a hypoxic tumor microenvironment, increased oxidative stress, and an immune suppressive milieu. These processes promote the neuro-inflammatory tumor microenvironment which can lead to the loss of blood-brain barrier (BBB) integrity. The consequences of a compromised BBB are deleteriously exposing the brain to potentially harmful concentrations of substances from the peripheral circulation, adversely affecting neuronal signaling, and abnormal immune cell infiltration; all of which can lead to disruption of brain homeostasis. In this review, we first describe the unique features of inflammation in CNS tumors. We then discuss the mechanisms of tumor-initiating neuro-inflammatory microenvironment and its impact on tumor invasion and progression. Finally, we also discuss potential pharmacological interventions that can be used to target neuro-inflammation in gliomas.

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Inhibitory CD161 receptor identified in glioma-infiltrating T cells by single-cell analysis

Cited by 277 publications

References 66 publications

Immunotherapy for Glioblastoma: Current Progress and Challenges

Immunotherapy for Glioblastoma: Current Progress and Challenges

A Pan-Cancer Analysis of CD161, a Potential New Immune Checkpoint

Targeting Neuroinflammation in Brain Cancer: Uncovering Mechanisms, Pharmacological Targets, and Neuropharmaceutical Developments

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