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Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors.

ABSTRACT: Formation of polyploid or aneuploid cells is a pathological hallmark of malignant tumors. Cell cycle checkpoint mechanisms play a crucial role in ensuring genomic integrity during mitosis, avoiding the generation of aneuploid cells. Additionally, cancer cell DNA ploidy is subjected to extrinsic controls operated by activation of adaptive immune responses mediated by T cells. NK cells exert a central role in the innate anticancer immunity; however, the mechanisms involved in the recognition of tumor cells by NK cells have not been fully elucidated. Herein, we report that drug-induced polyploidy in cancer cells activates antitumor responses mediated by NK cells. Thus, hyperploidy-inducing chemotherapeutic agents strongly upregulate the tumor expression of ligands for the NK cell activating receptors NKG2D and DNAM-1. Drug-induced hyperploidy modulated the repertoire of activating receptors and the cytokine profile of NK cells, rendering tumor cells more susceptible to NK cell-mediated lysis through the activation of NKG2D and DNAM-1 receptors. In addition, hyperploidization stimulated the production of IL-2 by CD4 T cells, which induced NK cell proliferation and activity. The stimulation of MICA, a key NKG2D ligand, in hyperploid cells was mainly mediated by ATM protein kinase. Likewise, pharmacological inhibition of key regulators of endoplasmic reticulum stress in certain cell models supports a role for this pathway in NKG2D ligand upregulation. Overall, our findings indicate that, besides the cytotoxic effect on tumor cells, the therapeutic activity of anti-mitotic drugs may be mediated by the induction of a coordinated antitumor immune response involving NK and T cells.

SUBMITTER: Acebes-Huerta A

PROVIDER: S-EPMC4801427 | biostudies-literature | 2016 Feb

REPOSITORIES: biostudies-literature

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Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors.

Acebes-Huerta Andrea A Lorenzo-Herrero Seila S Folgueras Alicia R AR Huergo-Zapico Leticia L Lopez-Larrea Carlos C López-Soto Alejandro A Gonzalez Segundo S

Oncoimmunology 20150812 2

Formation of polyploid or aneuploid cells is a pathological hallmark of malignant tumors. Cell cycle checkpoint mechanisms play a crucial role in ensuring genomic integrity during mitosis, avoiding the generation of aneuploid cells. Additionally, cancer cell DNA ploidy is subjected to extrinsic controls operated by activation of adaptive immune responses mediated by T cells. NK cells exert a central role in the innate anticancer immunity; however, the mechanisms involved in the recognition of tu ...[more]

PMID: 27057443

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Project description:Sarcomas are malignancies of mesenchymal origin that occur in bone and soft tissues. Many are chemo- and radiotherapy resistant, thus conventional treatments fail to increase overall survival. Natural Killer (NK) cells exert anti-tumor activity upon detection of a complex array of tumor ligands, but this has not been thoroughly explored in the context of sarcoma immunotherapy. In this study, we investigated the NK cell receptor/ligand immune profile of primary human sarcoma explants. Analysis of tumors from 32 sarcoma patients identified the proliferative marker PCNA and DNAM-1 ligands CD112 and/or CD155 as commonly expressed antigens that could be efficiently targeted by genetically modified (GM) NK cells. Despite the strong expression of CD112 and CD155 on sarcoma cells, characterization of freshly dissociated sarcomas revealed a general decrease in tumor-infiltrating NK cells compared to the periphery, suggesting a defect in the endogenous NK cell response. We also applied a functional screening approach to identify relevant NK cell receptor/ligand interactions that induce efficient anti-tumor responses using a panel NK-92 cell lines GM to over-express 12 different activating receptors. Using GM NK-92 cells against primary sarcoma explants (n = 12) revealed that DNAM-1 over-expression on NK-92 cells led to efficient degranulation against all tested explants (n = 12). Additionally, NKG2D over-expression showed enhanced responses against 10 out of 12 explants. These results show that DNAM-1+ or NKG2D+ GM NK-92 cells may be an efficient approach in targeting sarcomas. The degranulation capacity of GM NK-92 cell lines was also tested against various established tumor cell lines, including neuroblastoma, Schwannoma, melanoma, myeloma, leukemia, prostate, pancreatic, colon, and lung cancer. Enhanced degranulation of DNAM-1+ or NKG2D+ GM NK-92 cells was observed against the majority of tumor cell lines tested. In conclusion, DNAM-1 or NKG2D over-expression elicited a dynamic increase in NK cell degranulation against all sarcoma explants and cancer cell lines tested, including those that failed to induce a notable response in WT NK-92 cells. These results support the broad therapeutic potential of DNAM-1+ or NKG2D+ GM NK-92 cells and GM human NK cells for the treatment of sarcomas and other malignancies.

Dataset Information

Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors.

Publications

Drug-induced hyperploidy stimulates an antitumor NK cell response mediated by NKG2D and DNAM-1 receptors.

Similar Datasets

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