Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis

Lo, Hin Ching; Xu, Zhan; Kim, Ik Sun; Pingel, Bradley; Aguirre, Sergio; Kodali, Srikanth; Li, Jun; Zhang, Weijie; Muscarella, Aaron M.; Hein, Sarah Maria von; Krupnick, Alexander S.; Neilson, Joel R.; Paust, Silke; Rosen, Jeffrey M.; Wang, Hai; Zhang, Xiang H.-F.

doi:10.1038/s43018-020-0068-9

Cited by 86 publications

(55 citation statements)

References 53 publications

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“…In particular, EMT is associated with early dissemination in a number of genetically engineered mouse models [185][186][187]. One potential explanation is that EMT may be advantageous for tumor cells in inhospitable microenvironments, particularly to establish a pre-metastatic niche [188], evade immune cells [189,190], or resist drug treatment. Indeed, Fischer et al and Zheng et al have reported that EMT is dispensable for metastasis in mouse models but associated with chemoresistance [191,192].…”

Section: Emt In Cancer Metastasismentioning

confidence: 99%

The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems

et al. 2021

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The epithelial-mesenchymal transition (EMT) is intrinsically linked to alterations of the intracellular cytoskeleton and the extracellular matrix. After EMT, cells acquire an elongated morphology with front/back polarity, which can be attributed to actin-driven protrusion formation as well as the gain of vimentin expression. Consequently, cells can deform and remodel the surrounding matrix in order to facilitate local invasion. In this review, we highlight recent bioengineering approaches to elucidate EMT and functional changes in the cytoskeleton. First, we review transitions between multicellular clusters and dispersed individuals on planar surfaces, which often exhibit coordinated behaviors driven by leader cells and EMT. Second, we consider the functional role of vimentin, which can be probed at subcellular length scales and within confined spaces. Third, we discuss the role of topographical patterning and EMT via a contact guidance like mechanism. Finally, we address how multicellular clusters disorganize and disseminate in 3D matrix. These new technologies enable controlled physical microenvironments and higher-resolution spatiotemporal measurements of EMT at the single cell level. In closing, we consider future directions for the field and outstanding questions regarding EMT and the cytoskeleton for human cancer progression.

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Section: Emt In Cancer Metastasismentioning

confidence: 99%

The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems

et al. 2021

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“…T cells are senescent, tolerant, exhausted, and anergic due to the immunosuppressive glioblastoma TME [ 40 , 47 ]. NK cells are important as immune effectors of the first line of defense against tumor cells and have been shown to control metastasis by eliminating circulating cancer cells [ 48 ]. The proposed mechanisms for the functional inactivation of tumor-associated NK cells are the overexpression of Fas ligand, the loss of mRNA for granzyme B [ 49 ], and the decrease of CD16 and its associated zeta chain [ 50 , 51 , 52 ].…”

Section: The Immunosuppressive Microenvironment Of Glioblastomamentioning

confidence: 99%

Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development

Majc

Novak

Kopitar-Jerala

et al. 2021

Cells

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Glioblastoma is the most common brain malignant tumor in the adult population, and immunotherapy is playing an increasingly central role in the treatment of many cancers. Nevertheless, the search for effective immunotherapeutic approaches for glioblastoma patients continues. The goal of immunotherapy is to promote tumor eradication, boost the patient’s innate and adaptive immune responses, and overcome tumor immune resistance. A range of new, promising immunotherapeutic strategies has been applied for glioblastoma, including vaccines, oncolytic viruses, immune checkpoint inhibitors, and adoptive cell transfer. However, the main challenges of immunotherapy for glioblastoma are the intracranial location and heterogeneity of the tumor as well as the unique, immunosuppressive tumor microenvironment. Owing to the lack of appropriate tumor models, there are discrepancies in the efficiency of various immunotherapeutic strategies between preclinical studies (with in vitro and animal models) on the one hand and clinical studies (on humans) on the other hand. In this review, we summarize the glioblastoma characteristics that drive tolerance to immunotherapy, the currently used immunotherapeutic approaches against glioblastoma, and the most suitable tumor models to mimic conditions in glioblastoma patients. These models are improving and can more precisely predict patients’ responses to immunotherapeutic treatments, either alone or in combination with standard treatment.

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“…Second, in many types of cancer, NK cells exhibit an altered phenotype and hypo-functionality ( 26 , 27 ). Third, in mice, resistance to NK cell killing favors polyclonal metastasis ( 28 ). Several mechanisms contribute to NK cell exhaustion, including modulating adhesion and epithelial genes, decreasing the expression of NK cell-activating ligands ( 28 ), and the suppressive effects of regulatory immune cells and soluble factors within the TME ( 29 ).…”

Section: Cytotoxic T Lymphocytes and Nk Cells In Cancermentioning

confidence: 99%

Natural Killer Cell Interactions With Myeloid Derived Suppressor Cells in the Tumor Microenvironment and Implications for Cancer Immunotherapy

Zalfa

Paust

2021

Front. Immunol.

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The tumor microenvironment (TME) is a complex and heterogeneous environment composed of cancer cells, tumor stroma, a mixture of tissue-resident and infiltrating immune cells, secreted factors, and extracellular matrix proteins. Natural killer (NK) cells play a vital role in fighting tumors, but chronic stimulation and immunosuppression in the TME lead to NK cell exhaustion and limited antitumor functions. Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of myeloid cells with potent immunosuppressive activity that gradually accumulate in tumor tissues. MDSCs interact with innate and adaptive immune cells and play a crucial role in negatively regulating the immune response to tumors. This review discusses MDSC-mediated NK cell regulation within the TME, focusing on critical cellular and molecular interactions. We review current strategies that target MDSC-mediated immunosuppression to enhance NK cell cytotoxic antitumor activity. We also speculate on how NK cell-based antitumor immunotherapy could be improved.

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Resistance to natural killer cell immunosurveillance confers a selective advantage to polyclonal metastasis

Cited by 86 publications

References 53 publications

The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems

The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems

Immunotherapy of Glioblastoma: Current Strategies and Challenges in Tumor Model Development

Natural Killer Cell Interactions With Myeloid Derived Suppressor Cells in the Tumor Microenvironment and Implications for Cancer Immunotherapy

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