Cell-in-cell Structures Formed between Human Cancer Cell Lines and the Cytotoxic Regulatory T-cell Line HOZOT

Takeuchi, Makoto; Inoue, Toshiya; Otani, Takeshi; Yamasaki, Fumiyuki; Nakamura, Shuji; Kibata, Masayoshi

doi:10.1093/jmcb/mjq002

Cited by 27 publications

(46 citation statements)

References 31 publications

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“…Although the biological properties of cell-in-cell structures remain unclear, the cell-in-cell activity by which immune cells penetrate the cytoplasm of tumor cells has been shown to result in programmed cell-in-cell death45. HOZOT cells are a novel cord blood–derived line of Tregs that exhibit multiple properties, such as cytotoxic activity and cell-in-cell activity against human tumor cells5. These findings have led to considerable recent research exploring the therapeutic effects of combining HOZOT cells and oncolytic viruses.…”

Section: Discussionmentioning

confidence: 99%

“…HOZOT cells were previously established from human umbilical cord blood6 and characterized as a cytotoxic Treg line with cell-in-cell activity5. HOZOT cells were maintained over mouse normal stromal ST2 cells (purchased from the RIKEN BioResource Center [Ibaraki, Japan]) and cultured in RPMI-1640 medium supplemented with 10% fetal bovine serum, 100 U/mL penicillin, and 100 mg/mL streptomycin.…”

Section: Methodsmentioning

confidence: 99%

“…This process reflects one of the mechanisms tumor cells employ to evade antitumor immunosurveillance3. However, it was recently reported that penetration of tumor cells by immune cells also represents a special form of immune attack, resulting in target cell death as well as self-destruction of the invading immune cells45.…”

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confidence: 99%

“…HOZOT cells exhibit cytotoxic activity against various human cancer cell lines but not normal human cells. Furthermore, HOZOT cells can actively penetrate target cancer cells and form cell-in-cell structures, which may be one of the mechanisms by which HOZOT cells exert cytotoxicity against cancer cells5. This unique cell-in-cell invasive property led us to examine the potential of using HOZOT cells as tumor-tropic carriers of biologics such as oncolytic viruses.…”

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confidence: 99%

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Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Onishi

Tazawa

Hashimoto

et al. 2016

Sci Rep

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“Cell-in-cell” denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35–loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

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Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Onishi

Tazawa

Hashimoto

et al. 2016

Sci Rep

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“…Makoto Takeuchi et al also reported that HOZOT cells, a type of cytotoxic regulatory cells, actively penetrated into target tumor cells. It is proposed that HOZOT cells within tumor cells may exert a cytotoxic effect against the target cells partially via similar caspase-3 dependent pathway [11]. These results indicate that heterotypic cell-in-cell structures exhibit distinct biological characteristics and significance compared to entosis or cannibalism.…”

Section: Introductionmentioning

confidence: 95%

Prevalence of Heterotypic Tumor/Immune Cell-In-Cell Structure In Vitro and In Vivo Leading to Formation of Aneuploidy

Chen

Wang

et al. 2013

PLoS ONE

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Cell-in-cell structures refer to a unique phenomenon that one living cell enters into another living cell intactly, occurring between homotypic tumor cells or tumor (or other tissue cells) and immune cells (named as heterotypic cell-in-cell structure). In the present study, through a large scale of survey we observed that heterotypic cell-in-cell structure formation occurred commonly in vitro with host cells derived from different human carcinomas as well as xenotypic mouse tumor cell lines. Most of the lineages of human immune cells, including T, B, NK cells, monocytes as well as in vitro activated LAK cells, were able to invade tumor cell lines. Poorly differentiated stem cells were capable of internalizing immune cells as well. More significantly, heterotypic tumor/immune cell-in-cell structures were observed in a higher frequency in tumor-derived tissues than those in adjacent tissues. In mouse hepatitis models, heterotypic immune cell/hepatocyte cell-in-cell structures were also formed in a higher frequency than in normal controls. After in vitro culture, different forms of internalized immune cells in heterotypic cell-in-cell structures were observed, with one or multiple immune cells inside host cells undergoing resting, degradation or mitosis. More strikingly, some internalized immune cells penetrated directly into the nucleus of target cells. Multinuclear cells with aneuploid nucleus were formed in target tumor cells after internalizing immune cells as well as in situ tumor regions. Therefore, with the prevalence of heterotypic cell-in-cell structures observed, we suggest that shielding of immune cells inside tumor or inflammatory tissue cells implies the formation of aneuploidy with the increased multinucleation as well as fine-tuning of microenvironment under pathological status, which may define distinct mechanisms to influence the etiology and progress of tumors.

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Progress of Research in Cell‐in‐Cell Phenomena

Yang

2012

The Anatomical Record

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The discovery of a nonphagocytotic process of cell-in-cell phenomena can be traced to over a century ago. However, its biological significance remains poorly understood. Three types of cell-in-cell phenomena have been described so far, termed ''cannibalism,'' ''emperipolesis,'' and ''entosis.'' These three kinds of cell-in-cell phenomena, apart from a common feature of one cell internal to another, are distinct both cytologically and biologically. In this review, we discussed them in their morphology, cell recognition, penetration mechanisms, and physiological roles, respectively. Anat Rec,

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Cell-in-cell Structures Formed between Human Cancer Cell Lines and the Cytotoxic Regulatory T-cell Line HOZOT

Cited by 27 publications

References 31 publications

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Tumor-specific delivery of biologics by a novel T-cell line HOZOT

Prevalence of Heterotypic Tumor/Immune Cell-In-Cell Structure In Vitro and In Vivo Leading to Formation of Aneuploidy

Progress of Research in Cell‐in‐Cell Phenomena

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