Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells

Kim, Nayoung; Kim, Hun Sik

doi:10.3389/fimmu.2018.02041

Cited by 94 publications

(91 citation statements)

References 132 publications

(159 reference statements)

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“…Recent comprehensive reviews provide detailed descriptions and delineate the obstacles remaining in multiple NK-based treatments that have been developed and tested in preclinical and clinical trials. These reviews cover topics including cytokine therapy, hematopoietic stem cell transplantation (HSCT), adoptive cell transfer, and CAR-NK therapy (2,3,(22)(23)(24)(25). Here, we summarize recent pre-clinical and clinical evidence regarding NK cell expression of checkpoint molecules and some of the most recent NK-based immunotherapeutic strategies.…”

Section: Introduction Nk Cells and Cancermentioning

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: Introduction Nk Cells and Cancermentioning

confidence: 99%

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

2020

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“…CD28 is important for maximizing the NK-cell responses to acute T. gondii infection (68). In addition to a potential alteration of co-stimualtory signals, T. gondii could induce higher expression of co-inhibitory molecules TIGIT and CD96 (69), which could then inhibit NK-cell memory formation; however, we did not observe any significant increases in the expression of these molecules during secondary T. gondii infection (data not shown).…”

Section: Discussionmentioning

confidence: 69%

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

Ivanova

Mundhenke

Gigley

2019

Preprint

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22Natural Killer (NK) cells can develop memory-like features and contribute to long-term 23 immunity in mice and humans. NK cells are critical for protection against acute T. 24 gondii infection. However, whether they contribute to long-term immunity in response to this 25 parasite is unknown. We used a vaccine challenge model of parasite infection to address this 26 question and to define the mechanism by which NK cells are activated during secondary parasite 27 infection. We found NK cells were required for control of secondary infection. NK cells 28 increased in number at the infection site, became cytotoxic and produced IFNγ. Adoptive transfer 29 and NK-cell fate mapping revealed that T. gondii−experienced NK cells were not intrinsically 30 different from naïve NK cells with respect to their long-term persistence and ability to protect. 31 Thus, they did not develop memory-like characteristics. Instead, a cell-extrinsic mechanism may 32 control protective NK-cell responses during secondary infection. To test the involvement of a 33 cell-extrinsic mechanism, we used anti-IL-12p70 and IL-12p35 − / − mice and found that the 34 secondary NK-cell response was not fully dependent on IL-12. IL-23 depletion with anti-IL-35 23p19 in vivo significantly reduced the secondary NK-cell response, suggesting that both IL-12 36 and IL-23 were involved. Anti-IL-12p40 treatment, which blocks both IL-12 and IL-23, 37 eliminated the protective secondary NK-cell response, supporting this hypothesis. Our results 38 define a previously unknown protective role for NK cells during secondary T. gondii infection 39 that is dependent on IL-12 and IL-23. 40 to T. gondii. In the absence of CD4+ T cells, IFNγ produced by NK cells promotes CD8+ T-cell 65 activation (21). In the absence of CD8+ T cells, NK-cell IFNγ contributes to the activation of 66 CD4+ T cells (22). In addition to cytokine production, NK cells produce perforin and granzymes 67 in response to the parasite and its subcellular components (23)(24)(25)(26). 68 NK cells are clearly important for early control of T. gondii infection, yet their role in 69 long-term immunity has not been addressed. This is clinically important to understand because 70 there currently is no vaccine that elicits sterilizing immunity to the parasite (15, 27). A vaccine 71 targeting the stimulation of NK cells in addition to CD8+ T cells could therefore be more 72 beneficial long-term. In addition, T. gondii infection causes health complications in 73 immunodeficient patients, many of whom are T-cell deficient (e.g., HIV patients) (11). 74Discovering new ways to utilize NK cells could be therapeutically beneficial for these patients. 75In this study, we aimed to find whether NK cells contribute to long-term immunity 76 against T. gondii in a vaccine challenge setting. We also investigated whether NK cells 77 developed memory-like features in response to this vaccination. Lastly, we tested mechanisms 78 involved in the activation of NK cells during secondary challenge. We demonstrate that NK cells 79 a...

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“…Functionally exhausted NK cells show less proliferation, reduced cytolytic activity, and downregulated cytokine secretion, thus losing the ability to attack tumor cells. Therapeutic blockade of the immune checkpoint receptors or ligands with mAbs can restore the antitumor function of NK cells, which have shown great promise for NK-cell-based tumor immunotherapy (114).…”

Section: Releasing the Inhibition On Nk Cells By Targeting The Immunementioning

confidence: 99%

Targeting Natural Killer Cells for Tumor Immunotherapy

Zhang

Shi

2020

Front. Immunol.

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Natural killer (NK) cells are important innate cytotoxic lymphocytes with a rapid and efficient capacity to recognize and kill tumor cells. In recent years, adoptive transfer of autologous-or allogeneic-activated NK cells has become a promising cellular therapy for cancer. However, the therapeutic efficiency is encouraging in hematopoietic malignancies, but disappointing in solid tumors, for which the use of NK-cell-based therapies presents considerable challenges. It is difficult for NK cells to traffic to, and infiltrate into, tumor sites. NK cell function, phenotype, activation, and persistence are impaired by the tumor microenvironment, even leading to NK cell dysfunction or exhaustion. Many strategies focusing on improving NK cells' durable persistence, activation, and cytolytic activity, including activation with cytokines or analogs, have been attempted. Modifying them with chimeric antigen receptors further increases the targeting specificity of NK cells. Checkpoint blockades can relieve the exhausted state of NK cells. In this review, we discuss how the cytolytic and effector functions of NK cells are affected by the tumor microenvironment and summarize the various immunotherapeutic strategies based on NK cells. In particular, we discuss recent advances in overcoming the suppressive effect of the tumor microenvironment with the aim of enhancing the clinical outcome in solid tumors treated with NK-cell-based immunotherapy.

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Targeting Checkpoint Receptors and Molecules for Therapeutic Modulation of Natural Killer Cells

Cited by 94 publications

References 132 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?

The IL-12– and IL-23–Dependent NK-Cell Response is Essential for Protective Immunity Against SecondaryToxoplasma GondiiInfection

Targeting Natural Killer Cells for Tumor Immunotherapy

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