Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells

Chambers, Andrea M.; Lupo, Kyle B.; Matosevic, Sandro

doi:10.3389/fimmu.2018.02517

Cited by 66 publications

(52 citation statements)

References 107 publications

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“…One metabolite that is present at higher concentrations in the TME is adenosine. Studies show the inhibitory effect of adenosine accumulation in the TME on immune cell function in general, and NK cell activity, primarily through engagement with the adenosine receptor A 2A R (325,326). Adenosine signaling in the TME can reduce NK cell proliferation and activation, as well as its effector function (327)(328)(329).…”

Section: Modulating Tumor Metabolitesmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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The emergence of immunotherapy for cancer treatment bears considerable clinical promise. Nevertheless, many patients remain unresponsive, acquire resistance, or suffer dose-limiting toxicities. Immune-editing of tumors assists their escape from the immune system, and the tumor microenvironment (TME) induces immune suppression through multiple mechanisms. Immunotherapy aims to bolster the activity of immune cells against cancer by targeting these suppressive immunomodulatory processes. Natural Killer (NK) cells are a heterogeneous subset of immune cells, which express a diverse array of activating and inhibitory germline-encoded receptors, and are thus capable of directly targeting and killing cancer cells without the need for MHC specificity. Furthermore, they play a critical role in triggering the adaptive immune response. Enhancing the function of NK cells in the context of cancer is therefore a promising avenue for immunotherapy. Different NK-based therapies have been evaluated in clinical trials, and some have demonstrated clinical benefits, especially in the context of hematological malignancies. Solid tumors remain much more difficult to treat, and the time point and means of intervention of current NK-based treatments still require optimization to achieve long term effects. Here, we review recently described mechanisms of cancer evasion from NK cell immune surveillance, and the therapeutic approaches that aim to potentiate NK function. Specific focus is placed on the use of specialized monoclonal antibodies against moieties on the cancer cell, or on both the tumor and the NK cell. In addition, we highlight newly identified mechanisms that inhibit NK cell activity in the TME, and describe how biochemical modifications of the TME can synergize with current treatments and increase susceptibility to NK cell activity.

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Section: Modulating Tumor Metabolitesmentioning

confidence: 99%

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

2020

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“…cytokines and chemokines (25,26). CD56 bright CD16 dim/neg NK cells represent up to 10% of peripheral blood NK cells, are most frequently found in lymph nodes, and can be subdivided according to their CD16 expression into CD56 bright CD16 dim NK cells and CD56 bright CD16 neg NK cells (27)(28)(29). They mainly play an immunoregulatory role by abundantly producing cytokines, but can also become cytotoxic after activation, for example, by interleukins (24,28,(30)(31)(32)(33).…”

Section: Introductionmentioning

confidence: 99%

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

et al. 2020

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Obesity is accompanied by a systemic chronic low-grade inflammation as well as dysfunctions of several innate and adaptive immune cells. Recent findings emphasize an impaired functionality and phenotype of natural killer (NK) cells under obese conditions. This review provides a detailed overview on research related to overweight and obesity with a particular focus on NK cells. We discuss obesity-associated alterations in subsets, distribution, phenotype, cytotoxicity, cytokine secretion, and signaling cascades of NK cells investigated in vitro as well as in animal and human studies. In addition, we provide recent insights into the effects of physical activity and obesity-associated nutritional factors as well as the reduction of body weight and fat mass on NK cell functions of obese individuals. Finally, we highlight the impact of impaired NK cell physiology on obesity-associated diseases, focusing on the elevated susceptibility for viral infections and increased risk for cancer development and impaired treatment response.NK cells are large granular lymphocytes that mediate rapid innate immunity against viruses, bacteria, parasites, and tumor cells without prior sensitization. NK cells primarily develop and mature in the bone marrow, migrate through the bloodstream, and seed into secondary lymphoid organs, like thymus, spleen, and lymph nodes as well as in other peripheral tissues, like lung, liver, kidney, uterus, and the gastrointestinal tract (23). In blood, NK cells represent 1-6% of all leukocytes and comprise up to 15% of human peripheral blood mononuclear cells (PBMCs). Human NK cells have been defined by the expression of adhesion molecule CD56 and by the absence of the T cell marker CD3. Based on their expression level of CD56 and the Fcγ receptor CD16, NK cells are subdivided into different subpopulations. The two major and classically defined subsets are the CD56 dim CD16 bright NK cells and the CD56 bright CD16 dim/neg NK cells. CD56 dim CD16 bright NK cells represent about 90% of all NK cells and are predominantly found in peripheral blood (24). They are mostly responsible for cytotoxic activity and target cell killing but are also a source of pro-inflammatory Abbreviations: ACM, adipocyte-conditioned media; Adamts3, a disintegrin-like and metallopeptidase with thrombospondin type 1 motif, 3; AdipoR, adiponectin receptor; Anxa8, annexin A8; AT, adipose tissue; Bax, Bcl-2-associated X protein; Bcl, B-cell lymphoma; BMI, body mass index; CCR, CC chemokine receptor; Csf1r, colony stimulating factor 1 receptor; CX3CR1, C-X3-C-motif chemokine receptor 1; DNAM-1, DNAX accessory molecule-1; ESR, estrogen receptor; FasL, Fas ligand; IFN-γ, interferon; GM-CSF; granulocyte macrophage colony-stimulating factor; H6pd, hexose-6-phosphate dehydrogenase; Hk2, hexokinase 2; IL, interleukinIL-6R; interleukin-6 receptor; Il18rap, interleukin 18 receptor accessory protein; IP-10, interferon gamma-induced protein 10; JAK, Janus kinase; KIR, killer immunoglobulin-like receptor; Klra1, killer lectin-like receptor subfamil...

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“…In fact, membrane-bound IL-15 is currently the best activating cytokine (47), although membrane-bound IL-21 is becoming an interesting challenger (48,49). In any case, long-term cytokine treatment can lead to NK cell exhaustion, which will inhibit NK activity (50).…”

Section: Cytokines Mediate Nk Activationmentioning

confidence: 99%

“…Tumor cells, directly or by controlling non-transformed cells, modify the environment to make it immunosuppressive and avoid destruction by effector immune cells (25,26,50). We will discuss here some approaches that can reverse this "negative" microenvironment.…”

Section: Modifying the Target Microenvironmentmentioning

confidence: 99%

“…We will not discuss drugs that per se sensitize target cells to NK cells. Tumor-induced modifications include metabolic changes with the production of metabolites that negatively affect NK cell cytotoxicity, e.g., lactate (26,50). This is the classical metabolite produced by tumor cells under the Warburg effect: cells perform glycolysis even in the presence of ample oxygen (26).…”

Section: Modifying the Target Microenvironmentmentioning

confidence: 99%

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Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

et al. 2020

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The innate lymphocyte lineage natural killer (NK) is now the target of multiple clinical applications, although none has received an agreement from any regulatory agency yet. Transplant of naïve NK cells has not proven efficient enough in the vast majority of clinical trials. Hence, new protocols wish to improve their medical use by producing them from stem cells and/or modifying them by genetic engineering. These techniques have given interesting results but these improvements often hide that natural killers are mainly that: natural. We discuss here different ways to take advantage of NK physiology to improve their clinical activity without the need of additional modifications except for in vitro activation and expansion and allograft in patients. Some of these tactics include combination with monoclonal antibodies (mAb), drugs that change metabolism and engraftment of specific NK subsets with particular activity. Finally, we propose to use specific NK cell subsets found in certain patients that show increase activity against a specific disease, including the use of NK cells derived from patients.

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Tumor Microenvironment-Induced Immunometabolic Reprogramming of Natural Killer Cells

Cited by 66 publications

References 107 publications

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Unleashing Natural Killer Cells in the Tumor Microenvironment–The Next Generation of Immunotherapy?

Obesity-Associated Alterations of Natural Killer Cells and Immunosurveillance of Cancer

Non-Genetically Improving the Natural Cytotoxicity of Natural Killer (NK) Cells

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