The Paradoxical Role of NKG2D in Cancer Immunity

Sheppard, Sam; Ferry, Amir; Guedes, Joana; Guerra, Nadia

doi:10.3389/fimmu.2018.01808

Cited by 54 publications

(47 citation statements)

References 216 publications

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“…Dysfunctional NK cells have been described in settings of chronic inflammation such as NASH [84], viral hepatitis [85] and in the TME [86]. Reduced membrane expression of certain NKG2D ligands in HCC patients correlate with disease progression and early recurrence [87,88].…”

Section: Nk Cellsmentioning

confidence: 99%

Immune-based therapies for hepatocellular carcinoma

et al. 2020

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Hepatocellular carcinoma (HCC) is the third most frequent cause of cancer-related death. The immune-rich contexture of the HCC microenvironment makes this tumour an appealing target for immune-based therapies. Here, we discuss how the functional characteristics of the liver microenvironment can potentially be harnessed for the treatment of HCC. We will review the evidence supporting a therapeutic role for vaccines, cell-based therapies and immune-checkpoint inhibitors and discuss the potential for patient stratification in an attempt to overcome the series of failures that has characterised drug development in this disease area.

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Section: Nk Cellsmentioning

confidence: 99%

Immune-based therapies for hepatocellular carcinoma

et al. 2020

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“…HC likewise impaired HDACi and SCFA-induced MICA in cancer cells. The consequences of constitutive MICA expression are poorly understood since it may have dual roles on anti-tumor immunity (90). Treating cancer with HC and thus reducing MICA expression can result in tumor immune evasion.…”

Section: Discussionmentioning

confidence: 99%

Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells

et al. 2020

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Møller et al. Citrate Facilitates MICA Expression GRAPHICAL ABSTRACT | MGAT5 knockout (KO) in HEK293 cells induces metabolic changes resulting in increased intracellular UDP-GlcNAc, increased glycolysis, enhanced spare respiratory capacity and higher citrate flux from the mitochondria. MGAT5 KO cells express constitutively high MICA, mainly regulated on the transcriptional level through opening of the chromatin at the MICA promoter. MICA expression in MGAT5 KO cells is dependent on citrate turnover and histone acetylation. Blocking citrate flux inhibits MICA expression in numerous cancer cell lines, and we propose that this is a central metabolic regulation of MICA and immune surveillance.

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“…DAC also upregulates UL16-binding proteins 1, 2, and 3 (i.e., ULBP1, ULBP2, and ULBP3), another group of NKG2D ligands that are expressed in many cancers and in stressed/damaged tissues ( Fig. 1E) (15,16). These molecules have been identified as targets for tumor immunosurveillance by the innate immune system and may elicit antitumor immunity without the requirement for conventional MHC-restricted antigen presentation (17).…”

Section: Decitabine Upregulates Surface Immune Molecules Related To γmentioning

confidence: 99%

Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

Weng

Lin

et al. 2020

Preprint

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One Sentence Summary: DNA methyltransferase inhibitors potentiate the killing of lung cancer by γδ T cells through remodeling cytoskeletal-immune synaptic networks. 3 ABSTRACT γδ T cells are a distinct subgroup of T cells that bridge the innate and adaptive immune systems and can attack cancer or virus-infected cells in an MHC-unrestricted manner. Despite its antitumor ability in both autologous and allogeneic settings, earlier trials of adoptive γδ T cell transfer in solid tumors had limited success due to limitations in cell expansion and the lack of a strategy to modulate tumor lytic interactions between γδ T and cancer cells. Here, we show through quantitative surface proteomics and gene enrichment analyses that DNA methyltransferase inhibitors (DNMTis) upregulate multiple surface molecules related to γδ T cell activation in cancer cells. DNMTi treatment of human lung cancer potentiates tumor lysis by ex vivo-expanded γδ T cells using a clinical-grade expansion protocol developed by our team to enrich for the Vδ1 subset while preserving their antitumor effector functions. Mechanistically, DNMTis enhance immune synapse formation and stabilize the synaptic cleft to facilitate γδ Tmediated tumor lysis. Through integrated analysis of RNA-seq, DNA methylation, and ATACseq, we demonstrate that depletion of DNMTs induces coordinated pattern alterations of immune synaptic-cytoskeletal networks at the cancer side of the immune synapse. In addition, single-cell mass cytometry reveals enrichment of polyfunctional γδ T subsets by DNMTis. Combined DNMTi and adoptive γδ T transfer in a mouse lung cancer model offers a significant survival benefit. Consistently, the DNMTi-associated cytoskeleton signature identifies a subset of lung cancer patients with improved survival. Our results demonstrate that epigenetic mechanisms are crucial for cytoskeletal remodeling in cancer to potentiate immune attack and support a combinatorial strategy of DNMTis and γδ T cell-based immunotherapy in lung cancer management.

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The Paradoxical Role of NKG2D in Cancer Immunity

Cited by 54 publications

References 216 publications

Immune-based therapies for hepatocellular carcinoma

Immune-based therapies for hepatocellular carcinoma

Cytoplasmic Citrate Flux Modulates the Immune Stimulatory NKG2D Ligand MICA in Cancer Cells

Epigenetic therapy remodels the immune synaptic cytoskeleton to potentiate cancer susceptibility to γδ T cells

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