Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy

Jiang, Weiqin; He, Yinjun; He, Wenguang; Wu, Guosheng; Zhou, Xingping; Sheng, Qinsong; Zhong, Weixia; Lu, Yimin; Ding, Yongfeng; Qi, Lu; Yang, Feng; Hua, Hanju

doi:10.3389/fimmu.2020.622509

Cited by 191 publications

(179 citation statements)

References 95 publications

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“…T cell exhaustion refers to the loss of T cell functions in patients with common chronic infections and cancer. Patients with cancer normally possess a large number of T cells, but most of them are exhausted (28). We found that CD161 was positively correlated with marker genes of exhausted T cells, immune activating genes, and immunosuppressive genes in pan-cancer such as TIGIT, PDCD1, LAG3, CTLA4, STING1, CD96, and IDO1.…”

Section: Discussionmentioning

confidence: 76%

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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Section: Discussionmentioning

confidence: 76%

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

Zhou

Liu

et al. 2021

Front. Immunol.

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“…Indeed, one of the hallmarks of cancer is the functional impairment of T-cells caused by a plethora of suppressive determinants in the TME, which leads to T-cell exhaustion [ 23 , 24 , 25 , 26 , 27 ]. Chronic antigen stimulation in the TME and immunosuppressive cytokines lead to dysfunctional T-cells, which are characterized by a peculiar continuum of epigenetic and transcriptional alterations resulting in the expression of inhibitory receptors and loss of early differentiation markers [ 28 , 29 , 30 , 31 , 32 , 33 ].…”

Section: Introductionmentioning

confidence: 99%

Improving CAR T-Cell Persistence

Pietrobon

Todd

Goswami

et al. 2021

IJMS

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Over the last decade remarkable progress has been made in enhancing the efficacy of CAR T therapies. However, the clinical benefits are still limited, especially in solid tumors. Even in hematological settings, patients that respond to CAR T therapies remain at risk of relapsing due to several factors including poor T-cell expansion and lack of long-term persistence after adoptive transfer. This issue is even more evident in solid tumors, as the tumor microenvironment negatively influences the survival, infiltration, and activity of T-cells. Limited persistence remains a significant hindrance to the development of effective CAR T therapies due to several determinants, which are encountered from the cell manufacturing step and onwards. CAR design and ex vivo manipulation, including culture conditions, may play a pivotal role. Moreover, previous chemotherapy and lymphodepleting treatments may play a relevant role. In this review, the main causes for decreased persistence of CAR T-cells in patients will be discussed, focusing on the molecular mechanisms underlying T-cell exhaustion. The approaches taken so far to overcome these limitations and to create exhaustion-resistant T-cells will be described. We will also examine the knowledge gained from several key clinical trials and highlight the molecular mechanisms determining T-cell stemness, as promoting stemness may represent an attractive approach to improve T-cell therapies.

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“…This class of receptors can be targeted through mAbs to restore immune responses in cancer patients, a therapeutic strategy that has led to unprecedented long-term responses in a variety of cancers [ 75 ]. In T cell, expression of immune checkpoints such as PD-1, CTLA-4, TIM-3, TIGIT, or LAG3 is associated with functional exhaustion [ 76 ]. Although some of these receptors have been observed on NK cells, their implications for NK cell functions are only starting to be explored.…”

Section: T Cell-associated Immune Checkpointsmentioning

confidence: 99%

Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

Buckle

Guillerey

2021

Cancers

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The discovery of immune checkpoints provided a breakthrough for cancer therapy. Immune checkpoints are inhibitory receptors that are up-regulated on chronically stimulated lymphocytes and have been shown to hinder immune responses to cancer. Monoclonal antibodies against the checkpoint molecules PD-1 and CTLA-4 have shown early clinical success against melanoma and are now approved to treat various cancers. Since then, the list of potential candidates for immune checkpoint blockade has dramatically increased. The current paradigm stipulates that immune checkpoint blockade therapy unleashes pre-existing T cell responses. However, there is accumulating evidence that some of these immune checkpoint molecules are also expressed on Natural Killer (NK) cells. In this review, we summarize our latest knowledge about targetable NK cell inhibitory receptors. We discuss the HLA-binding receptors KIRS and NKG2A, receptors binding to nectin and nectin-like molecules including TIGIT, CD96, and CD112R, and immune checkpoints commonly associated with T cells such as PD-1, TIM-3, and LAG-3. We also discuss newly discovered pathways such as IL-1R8 and often overlooked receptors such as CD161 and Siglecs. We detail how these inhibitory receptors might regulate NK cell responses to cancer, and, where relevant, we discuss their implications for therapeutic intervention.

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Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy

Cited by 191 publications

References 95 publications

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

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

Improving CAR T-Cell Persistence

Inhibitory Receptors and Immune Checkpoints Regulating Natural Killer Cell Responses to Cancer

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