IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18

Oka, Naoto; Markova, Tzvetanka; Tsuzuki, Kenzo; Li, Wen; El‐Darawish, Yosif; Pencheva-Demireva, Magdalena; Yamanishi, Kyousuke; Yamanishi, Hiromichi; Sakagami, Masafumi; Tanaka, Yoshimasa; Okamura, Haruki

doi:10.1007/s00262-020-02553-4

Cited by 44 publications

(30 citation statements)

References 45 publications

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“…CCL3 and CCL4 are required for the intra-tumoral recruitment of cytotoxic NK cells and CD8 + T cells [9][10][11]. In the presence of IL-12, NK cells are activated, express CD69 and CD25, and can further proliferate in the tumor niche [12,13]. Activated Th1 and NK cells proliferate and infiltrate into the tumor, where Th1 cells support the effector functions of tumorspecific cytotoxic T cells [4,12,13].…”

Section: Il-12mentioning

confidence: 99%

“…In the presence of IL-12, NK cells are activated, express CD69 and CD25, and can further proliferate in the tumor niche [12,13]. Activated Th1 and NK cells proliferate and infiltrate into the tumor, where Th1 cells support the effector functions of tumorspecific cytotoxic T cells [4,12,13]. The IFN-γ, granzyme, and perforin secreted by cytotoxic NK and CD8 + T cells can induce the apoptosis of cancer cells and control tumor growth.…”

Section: Il-12mentioning

confidence: 99%

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IL-12 Family Cytokines in Cancer and Immunotherapy

Mirlekar

Pylayeva-Gupta

2021

Cancers

161

102

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The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.

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Section: Il-12mentioning

confidence: 99%

Section: Il-12mentioning

confidence: 99%

IL-12 Family Cytokines in Cancer and Immunotherapy

Mirlekar

Pylayeva-Gupta

2021

Cancers

161

102

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“…The IL-12-STAT4 axis is also involved in the regulation of IL-10 expression ( 54 , 55 ). In NK cells, IL-2 induction of IL-10 is essentially intact in the absence of STAT4 ( Figure 1 ), but IL-12 fails to induce IL-10 expression in STAT4 −/− NK cells.…”

Section: Molecular Mechanisms Controlling Il-10 Expression In Ilcsmentioning

confidence: 99%

IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

Sun

Wu²,

Zhang³

et al. 2021

Front. Immunol.

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Innate lymphoid cells (ILCs) are mainly composed of natural killer (NK) cells and helper-like lymphoid cells, which play a vital role in maintaining tissue homeostasis, enhancing adaptive immunity and regulating tissue inflammation. Alteration of the distribution and function of ILCs subgroups are closely related to the pathogenesis of inflammatory diseases and cancers. Interleukin-10 (IL-10) is a highly pleiotropic cytokine, and can be secreted by several cell types, among of which ILCs are recently verified to be a key source of IL-10. So far, the stable production of IL-10 can only be observed in certain NK subsets and ILC2s. Though the regulatory mechanisms for ILCs to produce IL-10 are pivotal for understanding ILCs and potential intervenes of diseases, which however is largely unknown yet. The published studies show that ILCs do not share exactly the same mechanisms for IL-10 production with helper T cells. In this review, the molecular mechanisms regulating IL-10 production in NK cells and ILC2s are discussed in details for the first time, and the role of IL-10-producing ILCs in diseases such as infections, allergies, and cancers are summarized.

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“…When NK cells are stimulated, nearly 100-fold expansion is observed in 10 days ( 43 ). Prolonged culture, however, leads to the accumulation of functionally altered or exhausted phenotype of NK cells, resulting in the limitation of NK cell-based immunotherapy ( 44 ). Regarding CD8 + αβ T cells, the proportion of tumor antigen-specific CD8 + αβ T cells in tumor-infiltrating T lymphocytes (TILs) is only 10% and it is difficult to expand a large number of functional tumor antigen-specific CD8 + T cells for adoptive immunotherapy ( 45 ).…”

Section: Discussionmentioning

confidence: 99%

Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells

et al. 2020

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Increasing attention has been paid to human γδ T cells expressing Vγ2Vδ2 T cell receptor (also termed Vγ9Vδ2) in the field of cancer immunotherapy. We have previously demonstrated that a novel bisphosphonate prodrug, tetrakis-pivaloyloxymethyl 2-(thiazole-2-ylamino)ethylidene-1,1-bisphosphonate (PTA), efficiently expands peripheral blood Vγ2Vδ2 T cells to purities up to 95–99% in 10–11 days. In the present study, we first examined the effect of PTA on farnesyl diphosphate synthase (FDPS) using liquid chromatography mass spectrometry (LC-MS) to analyze the mechanism underlying the PTA-mediated expansion of Vγ2Vδ2 T cells. We find that the prodrug induced the accumulation of both isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP), direct upstream metabolites of FDPS. This indicates that not only IPP but also DMAPP plays an important role in PTA-mediated stimulation of Vγ2Vδ2 T cells. We next analyzed TCR-independent cytotoxicity of Vγ2Vδ2 T cells. When human lung cancer cell lines were challenged by Vγ2Vδ2 T cells, no detectable cytotoxicity was observed in 40 min. The lung cancer cell lines were, however, significantly killed by Vγ2Vδ2 T cells after 4–16 h in an effector-to-target ratio-dependent manner, demonstrating that Vγ2Vδ2 T cell-based cell therapy required a large number of cells and longer time when tumor cells were not sensitized. By contrast, pulsing tumor cell lines with 10–30 nM of PTA induced significant lysis of tumor cells by Vγ2Vδ2 T cells even in 40 min. Similar levels of cytotoxicity were elicited by ZOL at concentrations of 100–300 μM, which were much higher than blood levels of ZOL after infusion (1–2 μM), suggesting that standard 4 mg infusion of ZOL was not enough to sensitize lung cancer cells in clinical settings. In addition, Vγ2Vδ2 T cells secreted interferon-γ (IFN-γ) when challenged by lung cancer cell lines pulsed with PTA in a dose-dependent manner. Taken together, PTA could be utilized for both expansion of Vγ2Vδ2 T cells ex vivo and sensitization of tumor cells in vivo in Vγ2Vδ2 T cell-based cancer immunotherapy. For use in patients, further studies on drug delivery are essential because of the hydrophobic nature of the prodrug.

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IL-12 regulates the expansion, phenotype, and function of murine NK cells activated by IL-15 and IL-18

Cited by 44 publications

References 45 publications

IL-12 Family Cytokines in Cancer and Immunotherapy

IL-12 Family Cytokines in Cancer and Immunotherapy

IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

Comparison of a Novel Bisphosphonate Prodrug and Zoledronic Acid in the Induction of Cytotoxicity in Human Vγ2Vδ2 T Cells

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