TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals

Wang, Feng; Wu, Shiji; Tang, Qing; Liu, Weiyong; Huang, Min; Yin, Botao; Huang, Jing; Mao, Lie; Lu, Yanfang; Sun, Ziyong

doi:10.1002/eji.201545480

Cited by 114 publications

(123 citation statements)

References 43 publications

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“…We found that TIGIT expression was significantly lower in adaptive NK cells compared with conventional NK cells. In a recent study, Wang et al have shown that different expression levels of TIGIT in NK cells from healthy individuals was associated with functional heterogeneity, and high TIGIT expression inversely correlated with IFN-γ production in response to IL-12 stimulation (20). Our results are in agreement with this study.…”

Section: Discussionmentioning

confidence: 99%

“…Recently, TIGIT was found to be highly expressed on tumor-infiltrating lymphocytes (TILs), and co-blockade of TIGIT and PD-1 synergistically augmented CD8 + T cell activity against autologous tumor cells (19). TIGIT is also expressed on polyclonal NK cells (20), but little is known with respect to how TIGIT regulates human NK cell function in the tumor microenvironment.…”

Section: Introductionmentioning

confidence: 99%

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Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

et al. 2016

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Human cytomegalovirus (CMV)-induced adaptive natural killer (NK) cells display distinct phenotypic and functional characteristics, including properties of immune memory. We hypothesized that these cells may be more resistant to suppression mediated by immune regulatory cell subsets, making them attractive for use in cancer therapy. Here we report that relative to conventional NK cells, adaptive NK cells express lower levels of the inhibitory receptor TIGIT which results in resistance to immune suppression mediated by myeloid-derived suppressor cells (MDSC), as derived from cytokine induction in normal blood or patients with myelodysplastic syndrome (MDS). In contrast, conventional NK cells were potently suppressed by MDSC, an effect abrogated completely by TIGIT blockade. Mechanistically, TIGIT signaling in NK cells after MDSC co-culture led to a decrease in the phosphorylation of ZAP70/Syk and ERK1/2. These effects were reversed by blocking TIGIT on NK cells or by inhibiting production of reactive oxygen species (ROS) by MDSC, the latter of which upregulated the TIGIT ligand CD155 on MDSC. Accordingly, the blunted cytotoxicity of NK cells co-cultured with MDSC against tumor cells could be reversed by blocking TIGIT or ROS production. Overall, our results show how adaptive NK cells arising in response to CMV infection can escape MDSC-mediated suppression, and defined TIGIT antagonists as a novel type of checkpoint inhibitor to enhance NK cell-mediated responses against cancer and infection.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

et al. 2016

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“…TIGIT is a novel key inhibitory checkpoint protein expressed on both NK and T cells with wide variation in its expression among individuals. [16, 17] Non-responding patients had elevated expression of TIGIT on T cells, which was even further upregulated in T cells and NK cells in patients with higher levels of IL-15. These data are consistent with recent in vitro reports that the blockade of the TIGIT pathway can increase NK cell IFNγ secretion and abrogate MDSC-mediated inhibition.…”

Section: Discussionmentioning

confidence: 99%

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

Bachanová

Sarhan

DeFor

et al. 2017

Cancer Immunol Immunother

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We report a novel phase 2 clinical trial in patients with poor prognosis refractory NHL testing the efficacy of haploidentical donor NK cell therapy (NK dose 0.5–3.27 × 107 NK cells/kg) with rituximab and IL-2.(clinicaltrials.gov NCT01181258) Therapy was tolerated without graft-versus-host-disease, cytokine release syndrome, or neurotoxicity. Of 15 evaluable patients, 4 had objective responses (26.6%) at 2 months: 2 had complete response lasting 3 and 9 months. Circulating donor NK cells persisted for at least 7 days after infusion at the level between 0.6–16 cells/µl. Responding patients had lower levels of circulating host derived Tregs (17±4 vs. 307±152 cells/µL; p=0.008) and myeloid derived suppressor cells (MDSC) at baseline (6.6%±1.4% vs. 13.0%±2.7%; p=0.06) than non-responding patients. Lower circulating Tregs correlated with low serum levels of IL-10 (R2=0.64; p<0.003; n=11), suggestive of an immunosuppressive milieu. Low expression of PD-1 on recipients T cells before therapy was associated with response. Endogenous IL-15 levels were higher in responders than non-responding patients at the day of NK cell infusion (mean±SEM: 30.0±4.0; n=4 vs 19.0±4.0 pg/ml; n=8; p=0.02) and correlated with NK cytotoxicity at day 14 as measured by expression of CD107a (R2=0.74; p=0.0009; n=12). In summary, our observations support development of donor NK cellular therapies for advanced NHL as a strategy to overcome chemoresistance. Therapeutic efficacy may be further improved through disruption of the immunosupressive environment and infusion of exogenous IL-15.

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“…29,30 TIGIT is an immune cell-specific immunoglobulin superfamily receptor of the CD28 family, which is present on the cell surface of 20%-90% of human NK cells with a median of 64%. 31 Similar to DNAM-1, TIGIT binds to CD112 and CD155; however, TIGIT affinity for CD112 and CD155 is higher compared with DNAM-1. 32 Moreover, TI-GIT is often coexpressed with DNAM-1 on NK cells, 31 making it likely that inhibition of NK cell function will dominate over activation when the NK cells encounter a target cell expressing CD155.…”

Section: Fig 2 Nk Cells Lyse Autologous Hiv-infected T Cells When Dmentioning

confidence: 93%

“…31 Similar to DNAM-1, TIGIT binds to CD112 and CD155; however, TIGIT affinity for CD112 and CD155 is higher compared with DNAM-1. 32 Moreover, TI-GIT is often coexpressed with DNAM-1 on NK cells, 31 making it likely that inhibition of NK cell function will dominate over activation when the NK cells encounter a target cell expressing CD155.…”

Section: Fig 2 Nk Cells Lyse Autologous Hiv-infected T Cells When Dmentioning

confidence: 93%

CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

Davis

Sowrirajan

Cogswell

et al. 2017

AIDS Research and Human Retroviruses

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Activation of primary CD4+ T cells induces the CD155, but not the CD112 ligands for the natural killer (NK) cell activation receptor (aNKR) CD226 [DNAX accessory molecule-1 (DNAM-1)]. We hypothesize that HIV productively infects activated CD4+ T cells and makes itself vulnerable to NK cell-mediated lysis when CD155 on infected T cells engages DNAM-1. The primary objective of this study is to determine whether CD155 alone or together with NKG2D ligands triggers autologous NK cell lysis of HIV-infected T cells and whether HIV modulates CD155. To determine whether HIV modulates this activation ligand, we infected ''activated'' CD4 + T cells with HIV in the absence or presence of Nef and/or Vpu and determined by flow cytometry whether they modulated CD155. To determine if CD155 alone, or together with NKG2D ligands, triggered NK cell lysis of autologous HIV-infected T cells, we treated purified NK cells with DNAM-1 and/or NKG2D blocking antibodies before the addition of purified autologous HIV-infected cells in cytolytic assays. Finally, we determined whether DNAM-1 works together with NKG2D as an NK cell coactivation receptor (caNKR) or whether they work independently as aNKRs to induce an NK cell lytic response. We demonstrate that HIV and specifically Nef and/or Vpu do not modulate CD155 on infected primary T cells; and both CD155 and NKG2D ligands synergize as aNKRs to trigger NK cell lysis of the infected cell.

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TIGIT expression levels on human NK cells correlate with functional heterogeneity among healthy individuals

Cited by 114 publications

References 43 publications

Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

Adaptive NK Cells with Low TIGIT Expression Are Inherently Resistant to Myeloid-Derived Suppressor Cells

Haploidentical natural killer cells induce remissions in non-Hodgkin lymphoma patients with low levels of immune-suppressor cells

CD155 on HIV-Infected Cells Is Not Modulated by HIV-1 Vpu and Nef but Synergizes with NKG2D Ligands to Trigger NK Cell Lysis of Autologous Primary HIV-Infected Cells

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