Targeting the TIGIT-PVR immune checkpoint axis as novel therapeutic option in breast cancer

Stamm, Hauke; Oliveira‐Ferrer, Leticia; Grossjohann, Eva-Maria; Muschhammer, Jana; Thaden, Vanessa; Brauneck, Franziska; Kischel, Roman; Müller, Volkmar; Bokemeyer, Carsten; Fiedler, Walter; Wellbrock, Jasmin

doi:10.1080/2162402x.2019.1674605

Cited by 66 publications

(64 citation statements)

References 61 publications

(75 reference statements)

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“…3 d). This distinction is supported by studies reporting increased affinity [ 23 , 24 ] and motility [ 32 ] of specific motor proteins interacting with mono- or short glutamylated MTs. Particularly, Kinesin-2 showed higher motility when MTs were modified with short Glu chains [ 32 ].…”

Section: Discussionmentioning

confidence: 91%

“…b hCMEC/D3-cells grown to confluence on chamber slides were incubated with EVs from MDA-MB231 or MDA-MB468 control or TTLL plus cells for 16 h. Then, MDA-MB231 or MDA-MB468 control cells loaded with CellTracker™ Green CMFDA were added and after 4 h, green fluorescent cells were counted. Mean ± SD of eight different determinations are shown [23,24] and motility [32] of specific motor proteins interacting with mono-or short glutamylated MTs. Particularly, Kinesin-2 showed higher motility when MTs were modified with short Glu chains [32].…”

Section: Discussionmentioning

confidence: 99%

“…Microarray analyses of TTLL4 messenger RNA (mRNA) levels were analysed in a cohort of 197 primary breast cancer tissue samples [24,25]. All patients were treated between 1991 and 2002 and were selected based on tissue availability.…”

Section: Microarray Datamentioning

confidence: 99%

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Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis

Arnold

Schattschneider

Schlüter

et al. 2020

J Exp Clin Cancer Res

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Background The survival rate is poor in breast cancer patients with brain metastases. Thus, new concepts for therapeutic approaches are required. During metastasis, the cytoskeleton of cancer cells is highly dynamic and therefore cytoskeleton-associated proteins are interesting targets for tumour therapy. Methods Screening for genes showing a significant correlation with brain metastasis formation was performed based on microarray data from breast cancer patients with long-term follow up information. Validation of the most interesting target was performed by MTT-, Scratch- and Transwell-assay. In addition, intracellular trafficking was analyzed by live-cell imaging for secretory vesicles, early endosomes and multiple vesicular bodies (MVB) generating extracellular vesicles (EVs). EVs were characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), Western blotting, mass spectrometry, and ingenuity pathway analysis (IPA). Effect of EVs on the blood-brain-barrier (BBB) was examined by incubating endothelial cells of the BBB (hCMEC/D3) with EVs, and permeability as well as adhesion of breast cancer cells were analyzed. Clinical data of a breast cancer cohort was evaluated by χ2-tests, Kaplan-Meier-Analysis, and log-rank tests while for experimental data Student’s T-test was performed. Results Among those genes exhibiting a significant association with cerebral metastasis development, the only gene coding for a cytoskeleton-associated protein was Tubulin Tyrosine Ligase Like 4 (TTLL4). Overexpression of TTLL4 (TTLL4plus) in MDA-MB231 and MDA-MB468 breast cancer cells (TTLL4plus cells) significantly increased polyglutamylation of β-tubulin. Moreover, trafficking of secretory vesicles and MVBs was increased in TTLL4plus cells. EVs derived from TTLL4plus cells promote adhesion of MDA-MB231 and MDA-MB468 cells to hCMEC/D3 cells and increase permeability of hCMEC/D3 cell layer. Conclusions These data suggest that TTLL4-mediated microtubule polyglutamylation alters exosome homeostasis by regulating trafficking of MVBs. The TTLL4plus-derived EVs may provide a pre-metastatic niche for breast cancer cells by manipulating endothelial cells of the BBB.

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Section: Discussionmentioning

confidence: 91%

Section: Discussionmentioning

confidence: 99%

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Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis

Arnold

Schattschneider

Schlüter

et al. 2020

J Exp Clin Cancer Res

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“…Another key finding of our paper is that the T-reg cells had a relatively higher TIGIT expression level in OS tumor. TIGIT and its ligand poliovirus receptor (PVR) have been emerging as novel promising targets in immunotherapy for many tumors such as breast cancer, lung cancer, hepatocellular carcinoma etc[41–43]. Tian reported that blockade of TIGIT prevented NK cell exhaustion and elicited potent anti-tumor immunity[44].…”

Section: Discussionmentioning

confidence: 99%

Single-cell RNA-seq reveals identity and heterogeneity of malignant osteoblast cells and TME in osteosarcoma

Zhou

2020

Preprint

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25Osteosarcoma (OS) has high heterogeneity and poor prognosis. In order to explore the 26 molecular mechanism of OS and the tumor micro-environment (TME) on OS, we 27 employed single-cell RNA-sequencing (scRNA-seq) on 110,745 individual cells from 28 65 chromosomal lesions, including structural variations (SVs) and copy number 66 alterations (CNAs); however, few recurrent point mutations in protein-encoding genes 67 have been identified in OS [11][12][13][14][15].Low expression of immune-associated genes is 68 another significant phenotype for OS [16]. How to convert the immunosuppressive 69 microenvironment into the one that favors the induction of antitumor immunity is 70 indispensable for effective cancer immunotherapy. 71Here, we employed single cell transcriptome approach to dissect the 72 heterogeneity of OS cells. We analyzed the transcriptomic profiles of a total of 73 110745 cells from 7 primary tumors, 2 lung metastatic and 2 recurrent OS tissues. We 74 first divided the OS cells into 5 sub-clusters and osteoclast into 3 subtypes. The 75 profiles of OS, OC and immune-system cells were analyzed. We found that the TME 76 of the recurrent and lung metastatic OS exhibited more significant suppressivity than 77 primary tumor tissue. Thus, the results in this study improve the understanding of the 78 immune-suppressivity observed in advanced OS including distant metastasis and 79 recurrence, and are potentially valuable in novel treatment strategy for OS. 80Of importance, we are the first to uncover that Treg cells in OS expressed 81 TIGIT. TIGIT is a coinhibitory receptor expressed on effector T cells, natural killer 82 (NK) cells, T regulatory cells (Treg) and T follicular helper (TFH) cells. It has gained 83 attention as a potential therapeutic target in wide variety of tumors[17-19]. The 84 antibodies of TIGIT, named BGB-A1217, had registered and recruited on August 85 2019. Here we explored the preclinical significance of blocking of TIGIT. 86 Method 87 Patients 88 The eleven patients for scRNA-seq analysis enrolled in this study were hospitalized 89 during the period of The study was approved by Shanghai Sixth People's Hospital Ethics Committee. Each 91 patient was provided a written signed consent. All patients were diagnosed according 92 to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines 93 in Oncology with the terms of Bone Cancer (Version 2.2019). Among 11 patients for 94 scRNA-seq, 7 were derived from the primary sites of patients who received traditional 95 first line combination chemotherapy for OS, including Adriamycin(ADM), 96 cisplatin(DDP), methotrexate(MTX) and Ifosfamide(IFO) and surgical therapy. 2 lung 97 metastatic patients and 2 recurrent patients all received the gemcitabine combined 98 with Docetaxel(GT) chemotherapy treatment. The BC17, one of the lung metastasis 99 patients, had enrolled in clinical trial NCT03676985 and undergone the anti-PD-L1 100 treatment for 6 times. For this clinical trial, all enrolled patients had finished the 101 neoadjuvant...

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“…Human NK cells, Tregs, memory T cells, and some CD8 + T cells, express TIGIT, while in the TME, tumor-infiltrating NK cells show upregulated TIGIT expression accompanied by decreased DNAM-1 levels. CD155 is barely expressed in healthy human tissues, but it is dramatically overexpressed in various cancers, being considered an independent prognostic marker for poor prognosis for patients with breast cancer ( 55 ). Binding of TIGIT with CD155 suppresses the NK cells' cytotoxicity and IFN-γ production, whereas blockade using an anti-TIGIT antibody could reverse this effect ( 56 ).…”

Section: The Key Nk Cell Checkpoint Receptors or Molecules That Contrmentioning

confidence: 99%

Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

Zhang¹,

Liu²

2020

Front. Immunol.

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Checkpoint blockade therapy, for example using antibodies against CTLA-4 and PD-1/PD-L1, relieves T cells from the suppression by inhibitory checkpoints in the tumor microenvironment; thereby achieving good outcomes in the treatment of different cancer types. Like T cells, natural killer (NK) cell inhibitory receptors function as checkpoints for NK cell activation. Upon interaction with their cognate ligands on infected cells, tumor cells, dendritic cells and regulatory T cells, signals from these receptors severely affect NK cells' activation and effector functions, resulting in NK cell exhaustion. Checkpoint inhibition with antagonistic antibodies (Abs) can rescue NK cell exhaustion and arouse their robust anti-tumor capacity. Most notably, the response to anti-PD-1 therapy can be enhanced by the increased frequency and activation of NK cells, thereby increasing the overall survival of patients with multiple types of cancer. In addition, rescue of NK cell activity could enhance adaptive T cells' anti-tumor activity. Some antagonistic Abs (e.g., anti-TIGIT and anti-NKG2A monoclonal Abs) have extraordinary potential in cancer therapy, as evidenced by their induction of potent anti-tumor immunity through recovering both NK and T cell function. In this review, we summarize the dysfunction of NK cells in the tumor microenvironment and the key NK cell checkpoint receptors or molecules that control NK cell function. We particularly focus on recent advances in the most promising strategies through blockade of NK cell checkpoints or their combination with other approaches to more effectively reject tumors.

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Targeting the TIGIT-PVR immune checkpoint axis as novel therapeutic option in breast cancer

Cited by 66 publications

References 61 publications

Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis

Tubulin Tyrosine Ligase Like 4 (TTLL4) overexpression in breast cancer cells is associated with brain metastasis and alters exosome biogenesis

Single-cell RNA-seq reveals identity and heterogeneity of malignant osteoblast cells and TME in osteosarcoma

Targeting NK Cell Checkpoint Receptors or Molecules for Cancer Immunotherapy

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