NK Cell Proliferation and Cytolytic Function Are Compromised In the Hypoxic Tumor Microenvironment

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4291-4291 ◽  
Author(s):  
Sonny Ang ◽  
Maria Lima Da Silva ◽  
Margaret Dawson ◽  
Matthew Figliola ◽  
Sourindra Maiti ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Chronic Hypoxia ◽  
Immune Cell ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Effector Function ◽  
Proliferative Capacity ◽  
Cd56 Expression ◽  
Hypoxic Tumor

Abstract Abstract 4291 Natural Killer (NK) cells have important and potent innate immunoregulatory and immune surveillance functions against tumor. The paradoxical coexistence of tumors and anti-tumor immune cells (“Hellstrom Paradox”) may in part be explained by the pathophysiology of the “hostile” tumor microenvironment which suppress immune-cell function, such as hypoxia, low pH, low tissue glucose, and the presence of immunosuppressive cytokines and metabolites. However, the effect of the malignant environment on the ability of NK cells to infiltrate tumor and exhibit effector function is largely unknown. Therefore, we investigated the ability of NK cells to operate under conditions of hypoxia. Importantly, NK cells showed a 1,000-fold reduction in proliferative capacity when grown under chronic hypoxia (4 weeks of 1% O2). In addition, there was a corresponding decrease in cytotoxicity as revealed by chromium release assay. This was in contrast to autologous T cells which could numerically expand under corresponding growth conditions. Expression profiling uncovers profound upregulation of hypoxia-inducible genes such as EGLN1(9.9x), EGLN3(52x), LDHA(11.5x), SLC2A1(30.5x), PDK1(16.8x), VEGFA(286x) and BNIP3(138x) in hypoxic NK cells. Protein expression confirmed these changes, as NK cells under normoxic culture produced 520 nmoles/million cells of ATP, while those under hypoxic culture managed only 100 nmoles/million cells. This is consistent with a bioenergetic switch from oxidative phosphorylation to glycosis resulting from PDK1 upregulation. NK cells in hypoxia produced 61 pg/mL of VEGF compared to 1480 pg/mL for NK cells in normoxia (20% O2), as determined by ELISA. The inability of NK cells to propagate under conditions of hypoxia may be due to a drop in mitochondrial content we observed when cells were exposed to chronic hypoxia, a potential mitophagic effects of BNIP3 upregulation. In addition to the poor proliferative capacity of NK cells under hypoxia, we also noted the loss of CD56 expression on hypoxic NK cells which is associated with loss of cytotoxicity. Sequence analysis reveals that miR-210 can bind to the 3′UTR of CD56 mRNA, targeting it for degradation. Therefore, we investigated whether miR-210 levels are upregulated in hypoxic NK cells and found that increased presence correlated with loss of CD56 expression. This leads to the conclusion that NK-cell immunotherapy may be improved by downregulating miR-210 levels. Indeed, our findings help shape strategies for obtaining robust and sustained NK-cell effector function for adoptive immunotherapy in the hypoxic tumor microenvironment. Disclosures: No relevant conflicts of interest to declare.

Multispecific targeting of glioblastoma with tumor microenvironment-responsive multifunctional engineered NK cells

2021 ◽  
Vol 118 (45) ◽  
pp. e2107507118
Author(s):  
Jiao Wang ◽  
Sandra Toregrosa-Allen ◽  
Bennett D. Elzey ◽  
Sagar Utturkar ◽  
Nadia Atallah Lanman ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Specific Activity ◽  
Antibody Fragment ◽  
Genetically Engineered ◽  
Local Concentration ◽  
Local Tumor

Tumor antigen heterogeneity, a severely immunosuppressive tumor microenvironment (TME) and lymphopenia resulting in inadequate immune intratumoral trafficking, have rendered glioblastoma (GBM) highly resistant to therapy. To address these obstacles, here we describe a unique, sophisticated combinatorial platform for GBM: a cooperative multifunctional immunotherapy based on genetically engineered human natural killer (NK) cells bearing multiple antitumor functions including local tumor responsiveness that addresses key drivers of GBM resistance to therapy: antigen escape, immunometabolic reprogramming of immune responses, and poor immune cell homing. We engineered dual-specific chimeric antigen receptor (CAR) NK cells to bear a third functional moiety that is activated in the GBM TME and addresses immunometabolic suppression of NK cell function: a tumor-specific, locally released antibody fragment which can inhibit the activity of CD73 independently of CAR signaling and decrease the local concentration of adenosine. The multifunctional human NK cells targeted patient-derived GBM xenografts, demonstrated local tumor site–specific activity in the tissue, and potently suppressed adenosine production. We also unveil a complex reorganization of the immunological profile of GBM induced by inhibiting autophagy. Pharmacologic impairment of the autophagic process not only sensitized GBM to antigenic targeting by NK cells but promoted a chemotactic profile favorable to NK infiltration. Taken together, our study demonstrates a promising NK cell–based combinatorial strategy that can target multiple clinically recognized mechanisms of GBM progression simultaneously.

scholarly journals NK Cells in the Tumor Microenvironment as New Potential Players Mediating Chemotherapy Effects in Metastatic Melanoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Cinzia Garofalo ◽  
Carmela De Marco ◽  
Costanza Maria Cristiani
Keyword(s):  
T Cells ◽  
Tumor Microenvironment ◽  
Nk Cells ◽  
Metastatic Melanoma ◽  
Targeted Delivery ◽  
Immune Cell ◽  
Nk Cell ◽  
Immune Checkpoints ◽  
Target Cells ◽  
Cytotoxic Lymphocytes

Until the last decade, chemotherapy was the standard treatment for metastatic cutaneous melanoma, even with poor results. The introduction of immune checkpoints inhibitors (ICIs) radically changed the outcome, increasing 5-year survival from 5% to 60%. However, there is still a large portion of unresponsive patients that would need further therapies. NK cells are skin-resident innate cytotoxic lymphocytes that recognize and kill virus-infected as well as cancer cells thanks to a balance between inhibitory and activating signals delivered by surface molecules expressed by the target. Since NK cells are equipped with cytotoxic machinery but lack of antigen restriction and needing to be primed, they are nowadays gaining attention as an alternative to T cells to be exploited in immunotherapy. However, their usage suffers of the same limitations reported for T cells, that is the loss of immunogenicity by target cells and the difficulty to penetrate and be activated in the suppressive tumor microenvironment (TME). Several evidence showed that chemotherapy used in metastatic melanoma therapy possess immunomodulatory properties that may restore NK cells functions within TME. Here, we will discuss the capability of such chemotherapeutics to: i) up-regulate melanoma cells susceptibility to NK cell-mediated killing, ii) promote NK cells infiltration within TME, iii) target other immune cell subsets that affect NK cells activities. Alongside traditional systemic melanoma chemotherapy, a new pharmacological strategy based on nanocarriers loaded with chemotherapeutics is developing. The use of nanotechnologies represents a very promising approach to improve drug tolerability and effectiveness thanks to the targeted delivery of the therapeutic molecules. Here, we will also discuss the recent developments in using nanocarriers to deliver anti-cancer drugs within the melanoma microenvironment in order to improve chemotherapeutics effects. Overall, we highlight the possibility to use standard chemotherapeutics, possibly delivered by nanosystems, to enhance NK cells anti-tumor cytotoxicity. Combined with immunotherapies targeting NK cells, this may represent a valuable alternative approach to treat those patients that do not respond to current ICIs.

scholarly journals Natural Killer Cells Are Present in Rag1−/− Mice and Promote Tissue Damage During the Acute Phase of Ischemic Stroke

2021 ◽  
Author(s):  
Leoni Rolfes ◽  
Tobias Ruck ◽  
Christina David ◽  
Stine Mencl ◽  
Stefanie Bock ◽  
...  
Keyword(s):  
Nk Cells ◽  
Natural Killer ◽  
Adoptive Transfer ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Subset ◽  
Neurological Deficits ◽  
In Vitro Assays ◽  
Experimental Stroke ◽  
Transfer Model

AbstractRag1−/− mice, lacking functional B and T cells, have been extensively used as an adoptive transfer model to evaluate neuroinflammation in stroke research. However, it remains unknown whether natural killer (NK) cell development and functions are altered in Rag1−/− mice as well. This connection has been rarely discussed in previous studies but might have important implications for data interpretation. In contrast, the NOD-Rag1nullIL2rgnull (NRG) mouse model is devoid of NK cells and might therefore eliminate this potential shortcoming. Here, we compare immune-cell frequencies as well as phenotype and effector functions of NK cells in Rag1−/− and wildtype (WT) mice using flow cytometry and functional in vitro assays. Further, we investigate the effect of Rag1−/− NK cells in the transient middle cerebral artery occlusion (tMCAO) model using antibody-mediated depletion of NK cells and adoptive transfer to NRG mice in vivo. NK cells in Rag1−/− were comparable in number and function to those in WT mice. Rag1−/− mice treated with an anti-NK1.1 antibody developed significantly smaller infarctions and improved behavioral scores. Correspondingly, NRG mice supplemented with NK cells were more susceptible to tMCAO, developing infarctions and neurological deficits similar to Rag1−/− controls. Our results indicate that NK cells from Rag1−/− mice are fully functional and should therefore be considered in the interpretation of immune-cell transfer models in experimental stroke. Fortunately, we identified the NRG mice, as a potentially better-suited transfer model to characterize individual cell subset-mediated neuroinflammation in stroke.

scholarly journals Sex- and age‐dependent alterations of splenic immune cell profile and NK cell phenotypes and function in C57BL/6J mice

2021 ◽  
Vol 18 (1) ◽  
Author(s):  
Kelly B. Menees ◽  
Rachael H. Earls ◽  
Jaegwon Chung ◽  
Janna Jernigan ◽  
Nikolay M. Filipov ◽  
...  
Keyword(s):  
Parkinson’S Disease ◽  
Parkinson's Disease ◽  
Sex Differences ◽  
Nk Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Spleen Weight ◽  
Age Related ◽  
And Function ◽  
Cell Phenotypes

Abstract Background Physiological homeostasis decline, immunosenescence, and increased risk for multiple diseases, including neurodegeneration, are all hallmarks of ageing. Importantly, it is known that the ageing process is sex-biased. For example, there are sex differences in predisposition for multiple age-related diseases, including neurodegenerative and autoimmune diseases. However, sex differences in age-associated immune phenotypes are not clearly understood. Results Here, we examined the effects of age on immune cell phenotypes in both sexes of C57BL/6J mice with a particular focus on NK cells. We found female-specific spleen weight increases with age and concordant reduction in the number of splenocytes per gram of spleen weight compared to young females. To evaluate sex- and age-associated changes in splenic immune cell composition, we performed flow cytometry analysis. In male mice, we observed an age-associated reduction in the frequencies of monocytes and NK cells; female mice displayed a reduction in B cells, NK cells, and CD8 + T cells and increased frequency of monocytes and neutrophils with age. We then performed a whole blood stimulation assay and multiplex analyses of plasma cytokines and observed age- and sex-specific differences in immune cell reactivity and basal circulating cytokine concentrations. As we have previously illustrated a potential role of NK cells in Parkinson’s disease, an age-related neurodegenerative disease, we further analyzed age-associated changes in NK cell phenotypes and function. There were distinct differences between the sexes in age-associated changes in the expression of NK cell receptors, IFN-γ production, and impairment of α-synuclein endocytosis. Conclusions This study demonstrates sex- and age-specific alterations in splenic lymphocyte composition, circulating cytokine/chemokine profiles, and NK cell phenotype and effector functions. Our data provide evidence that age-related physiological perturbations differ between the sexes which may help elucidate sex differences in age-related diseases, including neurodegenerative diseases, particularly Parkinson’s disease, where immune dysfunction is implicated in their etiology.

scholarly journals In Vitro Evaluation of CD276-CAR NK-92 Functionality, Migration and Invasion Potential in the Presence of Immune Inhibitory Factors of the Tumor Microenvironment

Cells ◽  
2021 ◽  
Vol 10 (5) ◽  
pp. 1020
Author(s):  
Stefan Grote ◽  
Guillermo Ureña-Bailén ◽  
Kenneth Chun-Ho Chan ◽  
Caroline Baden ◽  
Markus Mezger ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Solid Tumors ◽  
Immune Cells ◽  
Immune Cell ◽  
Nk Cell ◽  
Migration And Invasion ◽  
Cellular Immunotherapy ◽  
Knock Out ◽  
Immunosuppressive Tumor Microenvironment

Background: Melanoma is the most lethal of all skin-related cancers with incidences continuously rising. Novel therapeutic approaches are urgently needed, especially for the treatment of metastasizing or therapy-resistant melanoma. CAR-modified immune cells have shown excellent results in treating hematological malignancies and might represent a new treatment strategy for refractory melanoma. However, solid tumors pose some obstacles for cellular immunotherapy, including the identification of tumor-specific target antigens, insufficient homing and infiltration of immune cells as well as immune cell dysfunction in the immunosuppressive tumor microenvironment (TME). Methods: In order to investigate whether CAR NK cell-based immunotherapy can overcome the obstacles posed by the TME in melanoma, we generated CAR NK-92 cells targeting CD276 (B7-H3) which is abundantly expressed in solid tumors, including melanoma, and tested their effectivity in vitro in the presence of low pH, hypoxia and other known factors of the TME influencing anti-tumor responses. Moreover, the CRISPR/Cas9-induced disruption of the inhibitory receptor NKG2A was assessed for its potential enhancement of NK-92-mediated anti-tumor activity. Results: CD276-CAR NK-92 cells induced specific cytolysis of melanoma cell lines while being able to overcome a variety of the immunosuppressive effects normally exerted by the TME. NKG2A knock-out did not further improve CAR NK-92 cell-mediated cytotoxicity. Conclusions: The strong cytotoxic effect of a CD276-specific CAR in combination with an “off-the-shelf” NK-92 cell line not being impaired by some of the most prominent negative factors of the TME make CD276-CAR NK-92 cells a promising cellular product for the treatment of melanoma and beyond.

scholarly journals 789 Generation of a Bicycle NK-TICA™, a novel NK cell engaging molecule to enhance targeted tumor cytotoxicity

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A824-A824
Author(s):  
Fay Dufort ◽  
Christopher Leitheiser ◽  
Gemma Mudd ◽  
Julia Kristensson ◽  
Alexandra Rezvaya ◽  
...  
Keyword(s):  
Phage Display ◽  
Nk Cells ◽  
Natural Killer ◽  
Tumor Antigen ◽  
Cell Activation ◽  
Immune Cell ◽  
Nk Cell ◽  
High Affinity ◽  
Tumor Cytotoxicity ◽  
Immune Oncology

BackgroundNatural killer (NK) cells are immune cells that can detect and eliminate tumor cells and bridge innate to adaptive immune responses. Tumor specific activation of NK cells is thus an area of active investigation in immune oncology, but to date has relied on complex biologic modalities (e.g., antibodies, fusion proteins, or cell therapies), each of which has inherent disadvantages in this application. Thus, alternative approaches are warranted. Bicycle® are small (ca. 1.5 kDa), chemically synthetic, structurally constrained peptides discovered via phage display and optimized using structure-driven design and medicinal chemistry approaches. We have now applied this technology to identify Bicycles that bind specifically to the key activating receptors, NKp46 and CD16a. When chemically coupled to tumor antigen binding Bicycles this results in highly potent, antigen-dependent receptor activation and NK cell activation. We term this new class of fully synthetic molecules Bicycle® natural killer- tumor-targeted immune cell agonists (NK-TICAs™) and we will describe their discovery and evaluation in this presentation.MethodsUsing our unique phage display screening platform, we have identified high affinity, selective binders to NKp46 and CD16a. By conjugating the Bicycle® NK cell-engaging binders to a model tumor antigen EphA2-binding Bicycle®, we have developed a bifunctional Bicycle NK-TICA™ molecule. In in vitro functional assays, we evaluated the ability of the Bicycle NK-TICAs™ to induce NK cell activation as well as cell-mediated cytotoxicity and cytokine production in NK-tumor co-culture assays.ResultsWe have developed a novel modular compound with high affinity and selectivity to NK cell receptors with specific tumor targeting capability. We demonstrate potent, selective binding of our Bicycles to receptor-expressing cells and the capability of the bifunctional molecule to induce NK cell function. With Bicycle's novel NK-TICA™ compound, we demonstrate engagement of NK cells, specific activation and function of NK cells, and enhanced EphA2-expressing tumor cytotoxicity, in a dose dependent manner.ConclusionsBicycle NK-TICAs™ are novel therapeutic agents capable of enhancing the landscape of immune oncology. We hypothesize that utilization of Bicycle NK-TICA™ as a multifunctional immune cell engager will promote modulation of NK cells, and infiltration and anti-tumor activity of NK cells in solid tumors. The data presented here provide initial proof of concept for application of the Bicycle technology to drive NK cell-mediated tumor immunity.

scholarly journals 799 Neoantigen-cytokine-chemokine multifunctional natural killer cell engager for immunotherapy of solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A834-A834
Author(s):  
Xue Yao ◽  
Sandro Matosevic
Keyword(s):  
Tumor Microenvironment ◽  
Cell Therapy ◽  
Nk Cells ◽  
Natural Killer ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Nk Cell ◽  
Killer Cell ◽  
Nk Cell Therapy

BackgroundThe effectiveness of natural killer (NK) cell-based immunotherapy against solid tumors is limited by the lack of specific antigens and the immunosuppressive tumor microenvironment (TME). Glioblastoma multiforme (GBM) is one such heavily immunosuppressive tumor that has been particularly hard to target and remains without a viable treatment. The development of novel approaches to enhance the efficacy of NK cells against GBM is urgently needed. NK cell engagers (NKCE) have been developed to enhance the efficacy of NK cell therapy.MethodsTo improve the clinical efficacy of NK cell therapy, we are developing a new generation of multi-specific killer engagers, which consists of a neoantigen-targeting moiety, together with cytokine and chemokine-producing domains. Neoantigens are new antigens formed specifically in tumor cells due to genome mutations, making them highly specific tools to target tumor cells. Our engager has been designed to target Wilms' tumor-1 (WT-1), a highly specific antigen overexpressed in GBM among other solid tumors. This is done through the generation of an scFv specific targeting the complex of WT-1126-134/HLA-A*02:01 on the surface of GBM. On the NK cell side, the engager is designed to target the activating receptor NKp46. Incorporation of the cytokine IL-15 within the engager supports the maturation, persistence, and expansion of NK cells in vivo while favoring their proliferation and survival in the tumor microenvironment. Additionally, our data indicated that the chemokine CXCL10 plays an important role in the infiltration of NK cells into GBM, however, GBM tumors produce low levels of this chemokine. Incorporation of a CXCL10-producing function into our engager supports intratumoral NK cell trafficking by promoting, through their synthetic production, increased levels of CXCL10 locally in the tumor microenvironment.ResultsCollectively, this has resulted in a novel multifunctional NK cell engager, combining neoantigen-cytokine-chemokine elements fused to an activating domain-specific to NK cells, and we have investigated its ability to support and enhance NK cell-mediated cytotoxicity against solid tumors in vitro and in vivo against patient-derived GBM models. The multi-specific engager shows both high tumor specificity, as well as the ability to overcome NK cell dysfunction encountered in the GBM TME.ConclusionsWe hypothesize that taking advantage of our multi-functional engager, NK cells will exhibit superior ex vivo expansion, infiltration, and antitumor activity in the treatment of GBM and other solid tumors.

scholarly journals A Novel Method to Study the in Vivo Trafficking and Homing of Adoptively Transferred NK Cells in Rhesus Macaques and Humans

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 659-659 ◽  
Author(s):  
Jan Davidson-Moncada ◽  
Noriko Sato ◽  
Robert F Hoyt ◽  
Robert N Reger ◽  
Marvin Thomas ◽  
...  
Keyword(s):  
Nk Cells ◽  
Adoptive Transfer ◽  
Nk Cell ◽  
Conflicts Of Interest ◽  
Raji Cell ◽  
K562 Cells ◽  
Ct Imaging ◽  
Pet Ct ◽  
Hematological Cancers

Abstract Adoptive transfer of allogeneic or autologous natural killer (NK) cells is now being developed for therapy of both hematological and solid malignancies. The efficacy of NK immunotherapy to mediate anti-tumor effects will ultimately be dependent on their ability to traffic and home to the tumor microenvironment. Recent data suggest expanded NK cells are ineffective at homing to the bone marrow (BM) and lymph nodes (LN) where hematological malignancies reside. A variety of techniques to maintain and/or enforce expression of homing receptors in NK cells are now being explored in preclinical models to improve their localization to the BM and LN. Historically, xenogeneic human into mouse or mouse into mouse models have been utilized for preclinical development of adoptive NK transfer. These experiments often use fluorescent dye-labeled NK cells and require repeated invasive biopsies, which can be confounded by sampling error, or the requirement for post mortem analysis. Here we present a method to track in real time and in vivo adoptively infused zirconium-89 (89Zr) labelled NK cells by PET imaging. A rhesus macaque (RM) model was used for these preclinical experiments as RM and human NK cells have similar expansion kinetics, and have greater similarity than mice in their phenotype, function, and homing receptors and ligands. PBMCs collected from the PB of 13 RMs were enriched for NK cells by CD3+ T-cell depletion and were then expanded for 14 days by culturing with irradiated human EBV-LCL cells in X-VIVO 20 media containing 10% human AB serum and 500 IU/μl of human IL-2. RM NK cells expanded a mean 145±41 fold and contained >99% pure CD3- and CD56+ cells. The phenotype and tumor cytotoxicity of RM NK cells were similar to NK cells expanded from humans (n=3) using similar expansion cultures; at a 10:1 E:T ratio, 67% and 73% of K562 cells were lysed by RM and human NK cell respectively. To label NK cells, 89Zr was conjugated to oxine, which readily permeabilized the cellular membrane and was retained in the cells. Expanded NK cells from both humans and RM showed no changes in CD16 or CD56 expression for up to 6 days following radiolabeling. Human and RM NK cell viability 0 to 24 hours following radiolabelling was 60-100% then declined to 20-30% after 6 days. 89Zr retention by both human and RM NK cells was 75-80% in the first 24 hours of culture but gradually declined with time, decreasing to 20-30% after 7 days of culture. Culturing radiolabeled human NK cells for 24-36 hours with different cellular populations including Ramos and Raji cell lines and normal human PBMCs revealed no significant transfer of radioactivity (max 2% above baseline), establishing that 89Zr was not transferred from labeled to unlabeled cells. Oxine labeling did not alter the cytotoxicity of human or RM NK cells vs K562 cells compared to unlabeled controls. 89Zr-oxine labeling of expanded RM NK cells is currently being used to quantify NK cell trafficking and survival following adoptive transfer in autologous macaques. In these experiments, RM recipients of adoptively infused 89Zr labeled NK cells receive concurrent deferoxamine to chelate and then enhance renal excretion of any free 89Zr that is released from dead cells. In the experiments shown below, 13 x 107 autologous ex vivo expanded 89Zr-labeled RM NK cells were injected IV into a 5.7 kg RM and tracked by sequential PET/CT imaging for 7 days. Up to 1-hour post infusion, most NK cell activity was restricted to the lungs. By 4 hours, NK cells began to traffic from the lungs to the liver and spleen. By 2 days, NK cells were no longer detectable in the lungs and resided largely in the liver and spleen, where they remained for the remainder of the 7 day imaging period. During the entire observation period, little to no NK cell radioactivity was detected in the LN or BM. In conclusion, 89Zr oxine labelling of NK cells followed by PET/CT imaging represents a powerful tool to track the in vivo fate of adoptively transferred NK cells. The RM model presented here provides a method to evaluate and optimize various strategies aimed at altering the phenotype of NK cells, with the goal of improving their homing to the BM and LN where hematological cancers reside. These preclinical in vitro and in vivo data suggest this technology could be safely extended to humans and could be applied to other cellular populations besides NK cells. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals The ubiquitin-editing enzyme A20 controls NK cell homeostasis through regulation of mTOR activity and TNF

2019 ◽  
Vol 216 (9) ◽  
pp. 2010-2023 ◽  
Author(s):  
Jessica Vetters ◽  
Mary J. van Helden ◽  
Sigrid Wahlen ◽  
Simon J. Tavernier ◽  
Arne Martens ◽  
...  
Keyword(s):  
Cell Death ◽  
Nk Cells ◽  
Cell Function ◽  
Immune Cell ◽  
Nk Cell ◽  
Cell Homeostasis ◽  
Life And Death ◽  
Cytotoxic Molecules ◽  
Editing Enzyme ◽  
Mtor Activity

The ubiquitin-editing enzyme A20 is a well-known regulator of immune cell function and homeostasis. In addition, A20 protects cells from death in an ill-defined manner. While most studies focus on its role in the TNF-receptor complex, we here identify a novel component in the A20-mediated decision between life and death. Loss of A20 in NK cells led to spontaneous NK cell death and severe NK cell lymphopenia. The few remaining NK cells showed an immature, hyperactivated phenotype, hallmarked by the basal release of cytokines and cytotoxic molecules. NK-A20−/− cells were hypersensitive to TNF-induced cell death and could be rescued, at least partially, by a combined deficiency with TNF. Unexpectedly, rapamycin, a well-established inhibitor of mTOR, also strongly protected NK-A20−/− cells from death, and further studies revealed that A20 restricts mTOR activation in NK cells. This study therefore maps A20 as a crucial regulator of mTOR signaling and underscores the need for a tightly balanced mTOR pathway in NK cell homeostasis.

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