NK cell expression of Tim-3: First impressions matter

So, Edward; Khaladj-Ghom, Ariana; Ji, Yaping; Amin, Julian; Song, Yang; Burch, Erin; Zhou, Hua; Sun, Hong; Chen, Shaodong; Bentzen, Søren M.; Hertzano, Ronna; Zhang, Xiaoyu; Strome, Scott E.

doi:10.1016/j.imbio.2019.03.001

Cited by 42 publications

(33 citation statements)

References 40 publications

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“…Additionally, resistance to anti-PD-1 monotherapy was correlated with the upregulation of TIM-3 in mouse models of lung adenocarcinoma [22]. Similar findings have been mirrored on NK cells, with studies having demonstrated co-expression of PD-1 and TIM-3 on NK cells from patients with various cancers [23,24].…”

Section: Introductionmentioning

confidence: 70%

TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

Dao

Utturkar

Lanman

et al. 2020

Cancers

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Among natural killer (NK) cell receptors, the T-cell immunoglobulin and mucin-containing domain (TIM-3) has been associated with both inhibitory and activating functions, depending on context and activation pathway. Ex vivo and in vitro, expression of TIM-3 is inducible and depends on activation stimulus. Here, we report that TIM-3 expression can be downregulated on NK cells under specific conditions. When NK cells are exposed to cancer targets, they synergize with stimulation conditions to induce a substantial decrease in TIM-3 expression on their surface. We found that such downregulation occurs following prior NK activation. Downregulated TIM-3 expression correlated to lower cytotoxicity and lower interferon gamma (IFN-γ) expression, fueling the notion that TIM-3 might function as a benchmark for human NK cell dysfunction.

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Section: Introductionmentioning

confidence: 70%

TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

Dao

Utturkar

Lanman

et al. 2020

Cancers

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“…Figure 3A). The increased expression of CD57 and CD158b suggested that LAG3+ NK cells are more mature than LAG3-NK cells (15) and elevated surface expression of TIM3 indicated that LAG3+ NK cells were activated (16).…”

Section: Resultsmentioning

confidence: 99%

LAG3 is a Central Regulator of NK Cell Cytokine Production

Narayanan

Ahl

Bijin

et al. 2020

Preprint

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25Natural killer (NK) cells are innate effectors, which play a crucial role in controlling 26 viral infections. Administration of IFN-α has shown promising results as a therapeutic, 27 controlling HIV, and chronic viral hepatitis. However the downstream mechanisms by which 28 IFN-α mediates its anti-viral effects is largely unknown. In this investigation, we evaluated 29 the impact of IFN-α on peripheral blood NK cells from healthy donors. High dimensional 30 flow cytometry analysis of NK cell surface receptors following exposure to IFN-α showed an 31 increased expression of the check point inhibitor LAG3. Further characterization revealed 32 that LAG3 was expressed in a subset of NK cells with high expression of activation and 33 maturation markers. Assessment of metabolic pathways showed that LAG3+ NK cells had 34 enhanced rates of glycolysis and glycolytic capacity, suggesting that it is a primed effector 35 subset with enhanced glucose metabolism. Inhibition of LAG3 on NK cells using antibody in 36 vitro resulted in a profound increase in secretion of cytokines IFN-γ, TNF-α, MIP-1α and 37 MIP-1β, without affecting the cytotoxic activity. Taken together, these results showed that 38 LAG3 is a negative regulator of cytokine production by mature NK cells. 39 40 Introduction: 41 2 The plasmacytoid (pDC)-Natural Killer (NK) cell axis acts as a first line of defence by the 42 host against viral infections. pDCs secrete type I interferons upon recognizing virus-43 associated pathogen associated molecular patterns (PAMPs) through pattern recognition 44 receptors (PRRs). Type I interferons (IFN-I) bind to IFN (IFN-/) receptors on the surface 45 of NK cells to prime, activate and initiate mechanisms for the destruction of infected cells. 46 The subsequent stimulation of the IFN signalling pathway results in the increased expression 47 65 expression of LAG3, an inhibitory receptor, commonly associated with T cell exhaustion in 66 chronic infections and cancer. To date, the function of LAG3 in NK cells is not well 67 understood due to contrasting results from mouse and human NK cells. While studies using 68 knockout mouse models suggested a positive role for LAG3 in NK cell cytotoxicity, these 69 could not be successfully reproduced in human NK cells (10,11). High dimensional flow 70 cytometry analysis in these studies revealed that LAG3 expression marks a subset of mature 71 activated NK cells. Metabolic assays additionally showed that NK cells expressing LAG3 72 have enhanced glycolytic activity. Blockade of LAG3 enhanced cytokine production by 73 activated NK cells without altering their cytotoxicity. Taken together, these results 74 demonstrate that LAG3 is a negative regulator of cytokine production and a potential 75 therapeutic target for chronic viral infections. 76 77 78 3 Materials and methods: 79 Isolation and stimulation of NK cells: Blood samples from healthy volunteer donors were 80 obtained after approval by the National Healthcare Group Domain Specific Review Board, 81 Singapore (NHG DSRB Ref: 2000/0...

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“… 124 , 125 TIM-3 is expressed on nearly all mature CD56 dim CD16 + NK cells and is upregulated following stimulation with IL-12 and IL-18, and by IL-15 mediated NK cell maturation; 126 – 128 this suggests that TIM-3 acts as a marker for NK cell maturation or activation, and TIM-3 cross-linking can inhibit NK cell-mediated cytotoxicity. 129 , 130 Importantly, upregulation of TIM-3 has been found in gastric cancer, lung cancer, renal cancer, head and neck cancer, melanoma, schwannoma, follicular B-cell non-Hodgkin lymphoma, cervical cancer, prostate cancer, colorectal cancer, urothelial bladder carcinoma, esophageal cancer, and in the peripheral blood of patients with ovarian cancer. 35 , 93 , 131 – 143 The co-expression of PD-1 and TIM-3 correlates with acute myelogenous leukemia progression, suggesting that TIM-3 has potential as a prognostic biomarker for various cancers.…”

Section: Checkpoint Receptors and Ligands In Nk Cell Dysfunctionmentioning

confidence: 99%

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

Cao

Wang

Jin

et al. 2020

Sig Transduct Target Ther

105

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Recent studies have demonstrated the potential of natural killer (NK) cells in immunotherapy to treat multiple types of cancer. NK cells are innate lymphoid cells that play essential roles in tumor surveillance and control that efficiently kill the tumor and do not require the major histocompatibility complex. The discovery of the NK’s potential as a promising therapeutic target for cancer is a relief to oncologists as they face the challenge of increased chemo-resistant cancers. NK cells show great potential against solid and hematologic tumors and have progressively shown promise as a therapeutic target for cancer immunotherapy. The effector role of these cells is reliant on the balance of inhibitory and activating signals. Understanding the role of various immune checkpoint molecules in the exhaustion and impairment of NK cells when their inhibitory receptors are excessively expressed is particularly important in cancer immunotherapy studies and clinical implementation. Emerging immune checkpoint receptors and molecules have been found to mediate NK cell dysfunction in the tumor microenvironment; this has brought up the need to explore further additional NK cell-related immune checkpoints that may be exploited to enhance the immune response to refractory cancers. Accordingly, this review will focus on the recent findings concerning the roles of immune checkpoint molecules and receptors in the regulation of NK cell function, as well as their potential application in tumor immunotherapy.

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NK cell expression of Tim-3: First impressions matter

Cited by 42 publications

References 40 publications

TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

TIM-3 Expression Is Downregulated on Human NK Cells in Response to Cancer Targets in Synergy with Activation

LAG3 is a Central Regulator of NK Cell Cytokine Production

Immune checkpoint molecules in natural killer cells as potential targets for cancer immunotherapy

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