NKG2D- and T-cell receptor-dependent lysis of malignant glioma cell lines by human γδ T cells: Modulation by temozolomide and A disintegrin and metalloproteases 10 and 17 inhibitors

Chitadze, Guranda; Lettau, Marcus; Luecke, Stefanie; Wang, Ting; Janßen, Ottmar; Fürst, Daniel E.; Mytilineos, Joannis; Wesch, Daniela; Oberg, Hans‐Heinrich; Held‐Feindt, Janka; Kabelitz, Dieter

doi:10.1080/2162402x.2015.1093276

Cited by 59 publications

(57 citation statements)

References 60 publications

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“…S1 and S2). NKG2DL induction by TMZ has previously been reported in four other human glioma cell lines (52). We found that the NKG2DL induction was independent from cytotoxic or growth inhibitory effects and was achieved at clinically relevant concentrations of chemotherapeutic agents and low doses of IR.…”

Section: Discussionsupporting

confidence: 78%

NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma

Weiss

Schneider

Silginer

et al. 2018

Clinical Cancer Research

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NKG2D is a potent activating immune cell receptor, and glioma cells express the cognate ligands (NKG2DL). These ligands are inducible by cellular stress and temozolomide (TMZ) or irradiation (IR), the standard treatment of glioblastoma, could affect their expression. However, a role of NKG2DL for the efficacy of TMZ and IR has never been addressed. We assessed the effect of TMZ and IR on NKG2DL and in a variety of murine and human glioblastoma models, including glioma-initiating cells, and a cohort of paired glioblastoma samples from patients before and after therapy. Functional effects were studied with immune cell assays. The relevance of the NKG2D system for the efficacy of TMZ and IR was assessed in syngeneic orthotopic glioblastoma models with blocking antibodies and NKG2D knockout mice. TMZ or IR induced NKG2DL and in all glioblastoma models, and glioblastoma patient samples had increased levels of NKG2DL after therapy with TMZ and IR. This enhanced the immunogenicity of glioma cells in a NGK2D-dependent manner, was independent from cytotoxic or growth inhibitory effects, attenuated by O-methylguanine-DNA-methyltransferase (MGMT), and required the DNA damage response. The survival benefit afforded by TMZ or IR relied on an intact NKG2D system and was decreased upon inhibition of the NKG2D pathway. The immune system may influence the activity of convential cancer treatments with particular importance of the NKG2D pathway in glioblastoma. Our data provide a rationale to combine NKG2D-based immunotherapies with TMZ and IR. .

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Section: Discussionsupporting

confidence: 78%

NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma

Weiss

Schneider

Silginer

et al. 2018

Clinical Cancer Research

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“…Notably, zoledronate is commonly used for osteoporosis in post-menopausal women, thus it would be a suitable therapeutic tool in triggering the immune response in cancer and influencing MSC behavior. More importantly, selective inhibitors of ADAMs, which block the secretion of NKG2D-L from carcinomas, leukemic cells, and MSC, could be used to enhance tumor cell recognition [35,159]. These findings would suggest that MSC display several molecular targets suitable for therapy but no one of them is exclusively expressed by this cell population.…”

Section: Drugs That Can Influence Msc-mediated Immune Regulationmentioning

confidence: 99%

“…Several kinds, compositions, and modes of administration of anti-tumor vaccines have been used with different results [160,161,162,163,164,165,166,167]. More recently, the focus of anti-tumor vaccines has been moved from tumor cells to TME too [7,9,10,131,132,133,134,135,136,137,138,139,140,141,142,143,144,145,146,147,148,149,150,151,152,153,154,155,156,157,158,159,160,161,162,163,164,165,166,167,168,169,170,171,172,173,174,175]. Indeed, the possibility of targeting tumor endothelial cells or the VEGF signaling axis with specific vaccines has been assessed in preclinical studies, and clinical trials are ongoing [168].…”

Section: Msc As Target Cells For Anti-tumor Vaccinesmentioning

confidence: 99%

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

Poggi

Giuliani

2016

Vaccines

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The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC) activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT), a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

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“…Although shedding caused by the proteolytic activity of a disintegrin and metalloproteinase domain-containing protein (ADAM-10 and 17) regulated expression of ULBP2 (29), reduced expression of NKG2D-L by vemurafenib likely involves another mechanism. We showed that the reduction of ULBP2 on the cell surface of vemurafenib-treated melanoma cells was not due to shedding.…”

Section: Discussionmentioning

confidence: 99%

Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib

Frazao

Colombo

Fourmentraux-Neves

et al. 2017

Cancer Immunology Research

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Over 60% of human melanoma tumors bear a mutation in the gene. The most frequent mutation is a substitution at codon 600 (V600E), leading to a constitutively active BRAF and overactivation of the MAPK pathway. Patients harboring mutated BRAF respond to kinase inhibitors such as vemurafenib. However, these responses are transient, and relapses are frequent. Melanoma cells are efficiently lysed by activated natural killer (NK) cells. Melanoma cells express several stress-induced ligands that are recognized by activating NK-cell receptors. We have investigated the effect of vemurafenib on the immunogenicity of seven-mutated melanoma cells to NK cells and on their growth and sensitivity to NK-cell-mediated lysis. We showed that vemurafenib treatment modulated expression of ligands for two activating NK receptors, increasing expression of B7-H6, a ligand for NKp30, and decreasing expression of MICA and ULBP2, ligands for NKG2D. Vemurafenib also increased expression of HLA class I and HLA-E molecules, likely leading to higher engagement of inhibitory receptors (KIRs and NKG2A, respectively), and decreased lysis of vemurafenib-treated melanoma cell lines by cytokine-activated NK cells. Finally, we showed that whereas batimastat (a broad-spectrum matrix metalloprotease inhibitor) increased cell surface ULBP2 by reducing its shedding, vemurafenib lowered soluble ULBP2, indicating that BRAF signal inhibition diminished expression of both cell-surface and soluble forms of NKG2D ligands. Vemurafenib, inhibiting BRAF signaling, shifted the balance of activatory and inhibitory NK ligands on melanoma cells and displayed immunoregulatory effects on NK-cell functional activities. .

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NKG2D- and T-cell receptor-dependent lysis of malignant glioma cell lines by human γδ T cells: Modulation by temozolomide and A disintegrin and metalloproteases 10 and 17 inhibitors

Cited by 59 publications

References 60 publications

NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma

NKG2D-Dependent Antitumor Effects of Chemotherapy and Radiotherapy against Glioblastoma

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

Shifting the Balance of Activating and Inhibitory Natural Killer Receptor Ligands on BRAFV600E Melanoma Lines with Vemurafenib

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