Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway

Álvarez, Maite; Simonetta, Federico; Baker, Jeanette; Pierini, Antonio; Wenokur, Arielle S.; Morrison, Alyssa R; Murphy, William J.; Negrin, Robert S.

doi:10.1172/jci.insight.127729

Cited by 67 publications

(101 citation statements)

References 61 publications

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“…NK cells also undergo functional exhaustion when exposed to the conditions prevalent in the TME. These phenotypes in NK cells are induced by high expression of checkpoint ligands on tumors (such as Programmed death-ligand 1 (PD-L1) and HLA-E) (69,70), inhibitory cytokines and inhibitory soluble factors (such as TGF-β and IL-10) (71-73), hypoxia (74,75), exposure to tumor suppressor cells (i.e., Tregs, tumor associated macrophages, and MDSCs) (76)(77)(78), and sustained chronic activation (such as sustained activation through the activating NKG2D receptor) (79,80).…”

Section: The Tumor Microenvironment Restrains Nk Cell Activitymentioning

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: The Tumor Microenvironment Restrains Nk Cell Activitymentioning

confidence: 99%

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

2020

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“…NK cell maturation is activating receptor dependent. Recent studies investigating exhausted NK cells during chronic stimulation suggest that increased KLRG1 indicates NK cell exhaustion [25]. In this study, NKG2D interaction with high levels of NKG2D ligands results in increased KLRG1 expression and loss of NKG2D expression on the cells and NK cell exhaustion.…”

Section: Discussionmentioning

confidence: 62%

“…However, during chronic T. gondii infection NK cells develop a response that contributes to CD8+ T cell dysfunction thereby promoting parasite reactivation in mice. NK cells can develop immune exhaustion in the tumor microenvironment, after overstimulation and during HCV infection[24; 25; 26; 27]. Our results suggest that NK cells are not becoming exhausted, but are developing into cells that negatively regulate the CD8+ T cell responses during chronic T. gondii infection.…”

Section: Discussionmentioning

confidence: 91%

“…Moreover, NK cell depletion rescued mice from death by helping restore CD8+ T cell function in spleen and brain, helped maintain encystation of the parasite and enhanced the survival of chronically infected mice after secondary parasite challenge. Although, NK cells may lose the ability to produce IFNγ, our results suggest that unlike tumor, overstimulation and persistent HCV infection[24; 25; 26; 27], they are also gaining function that negatively regulates the adaptive response to chronic T. gondii infection. The mechanism by which they are causing this negative regulation is unclear and will be important in future studies.…”

Section: Discussionmentioning

confidence: 94%

“…This highlights their ability to not simply fall into the background once adaptive immunity is established, but also to continue to play a role in immunity after acute infections are resolved. NK cells have also been shown to become exhausted[24; 25; 26; 27]. This can occur in the tumor microenvironment, chronic stimulation and persistent HCV infection.…”

Section: Introductionmentioning

confidence: 99%

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NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronicToxoplasma gondiiinfection

Ivanova

Krempels

Denton

et al. 2019

Preprint

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12NK cells regulate CD4+ and CD8+ T cells in acute viral infection, vaccination and the 13 tumor microenvironment. NK cells also become exhausted in chronic activation settings. 14 The mechanisms causing these ILC responses and their impact on adaptive immunity are 15 unclear. CD8+ T cell exhaustion develops during chronic Toxoplasma gondii (T. gondii) 16 infection resulting in parasite reactivation and death. How chronic T. gondii infection 17 impacts the NK cell compartment is not known. We demonstrate that NK cells do not 18 exhibit hallmarks of exhaustion. Their numbers are stable and they do not express high 19 PD1 or LAG3. NK cell depletion with anti-NK1.1 is therapeutic and rescues chronic T. 20 gondii infected mice from CD8+ T cell exhaustion dependent death, increases survival 21 after lethal secondary challenge and reduces parasite reactivation. Anti-NK1.1 treatment 22increased polyfunctional CD8+ T cell responses in spleen and brain and reduced CD8+ T 23 cell apoptosis. Chronic T. gondii infection promotes the development of a modified NK 24 cell compartment, which does not exhibit normal NK cell behavior. This splenic CD49a-25 CD49b+NKp46+ NK cell population develops during the early chronic phase of infection 26 and increases through the late chronic phase of infection. They are Ly49 and TRAIL 27 negative and are enriched for expression of CD94/NKG2A and KLRG1. They do not 28 produce IFNγ, are IL-10 negative, do not increase PDL1 expression, but do increase 29CD107a on their surface. They are also absent from brain. Based on the NK cell receptor 30 phenotype we observed NKp46 and CD94-NKG2A cognate ligands were measured. 31Activating NKp46 (NCR1-ligand) ligand increased and NKG2A ligand Qa-1b expression 32 was reduced. Blockade of NKp46 also rescued the chronically infected mice from death. 33Immunization with a single dose non-persistent 100% protective T. gondii vaccination 34 did not induce this cell population in the spleen, suggesting persistent infection is 35 essential for their development. We hypothesize chronic T. gondii infection induces an 36NKp46 dependent modified NK cell population that reduces functional CD8+ T cells to 37 promote persistent parasite infection in the brain. NK cell targeted therapies could 38 enhance immunity in people with chronic infections, chronic inflammation and cancer. 39 40 103 Materials and methods 104Mice 105 C57BL/6 (B6), B6.129S6-IL-10 tm1Flv /J (IL-10-GFP Tiger) mice were purchased from The 106 Jackson Laboratory. All animals were housed under specific pathogen-free conditions at 107 the University of Wyoming Animal Facility. This study was carried out in strict 108 accordance following the recommendations in the Guide for the Care and Use of 109 Laboratory Animals of the National Institutes of Health. The University of Wyoming 110 Institutional Animal Care and Use Committee (IACUC) (PHS/NIH/OLAW assurance 111 number: A3216-01) approved all animal protocols. 112 113 T. gondii parasites and infection 114 130 Brain and spleen T cell isolation and stimulatio...

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NKG2D engagement on human NK cells leads to DNAM‐1 hypo‐responsiveness through different converging mechanisms

et al. 2022

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Natural killer (NK) cell activation is regulated by activating and inhibitory receptors that facilitate diseased cell recognition. Among activating receptors, NKG2D and DNAM-1 play a pivotal role in anticancer immune responses since they bind ligands upregulated on transformed cells. During tumor progression, however, these receptors are frequently downmodulated and rendered functionally inactive. Of note, NKG2D internalization has been associated with the acquisition of a dysfunctional phenotype characterized by the cross-tolerization of unrelated activating receptors. However, our knowledge of the consequences of NKG2D engagement is still incomplete. Here, by cytotoxicity assays combined with confocal microscopy, we demonstrate that NKG2D engagement on human NK cells impairs DNAM-1-mediated killing through two different converging mechanisms: by the upregulation of the checkpoint inhibitory receptor TIGIT, that in turn suppresses DNAM-1-mediated cytotoxic function, and by direct inhibition of DNAM-1-promoted signaling. Our results highlight a novel interplay between NKG2D and DNAM-1/TIGIT receptors that may facilitate neoplastic cell evasion from NK cell-mediated clearance.

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Regulation of murine NK cell exhaustion through the activation of the DNA damage repair pathway

Cited by 67 publications

References 61 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?

NK cells negatively regulate CD8 T cells to promote immune exhaustion and chronicToxoplasma gondiiinfection

NKG2D engagement on human NK cells leads to DNAM‐1 hypo‐responsiveness through different converging mechanisms

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