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Langerhans cells and dendritic cells are cytotoxic towards HPV16 E6 and E7 expressing target cells

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Abstract

Dendritic cells (DC) can be cytotoxic towards tumor cells by means of TNF family molecules expressed on the cell surface of activated DCs. Tumor cells expressing appropriate receptors are killed by DC, generating a source of antigen to be presented to the immune system. It has not been investigated whether Langerhans cells (LC) are selectively cytotoxic to tumor cells. This is of particular interest for epithelial tumor cells that physically interact with LC in vivo. Among epithelial tumors, the oncogenic process of cervical tumors is relatively well defined by their Human Papillomavirus (HPV) mediated etiology. To study whether HPV16 E6 and E7 expressions, otherwise observed in cervical tumor cells, can sensitize normal cervical epithelial cells to DC and LC mediated killing, the E6 and E7 genes were introduced by retroviral transfection, and cells were subsequently used as targets in cytotoxicity assays. Expression of cytotoxic molecules by effector cells was measured in response to the pro-inflammatory cytokine IFN-γ; cytotoxicity was established and concomitant expression of receptor molecules was assessed on target cells. A correlation between the shrinkage of HPV16 E6 and E7+ tumors versus DC and LC infiltration was evaluated in a murine model of cervical cancer. DC and LC proved to be equally cytotoxic towards E6 and E7 expressing cervical epithelial cells. IFN-γ induced TRAIL expression by DC and LC, and inhibition of TRAIL partially blocked cytotoxic effects. Expression of TRAIL decoy receptors was reduced following introduction of E6 and E7 into host cells. Shrinkage of HPV16 E6 and E7 expressing tumors correlated with infiltration by S100+ DC and LC, co-localizing with apoptotic mouse tumor cells. In conclusion, DC and LC mediated killing may be exploitable for anti-tumor treatment.

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Abbreviations

DC:

Dendritic cells

HPV:

Human Papillomavirus

IFN-γ:

Interferon-gamma

LC:

Langerhans cells

TGF-β:

Transforming growth factor-beta

TNF:

Tumor necrosis factor

TRAIL:

TNF- related apoptosis-inducing ligand

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Acknowledgment

This study was supported by Penny Severns Fund, Illinois Department of Public Health and NCI grants CA74397 and CA97296. WMK holds the Walter A. Richter Chair.

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Authors and Affiliations

  1. Department of Pathology/Oncology Institute, Loyola University Medical Center, Bldg 112, Rm 203, 2160 South 1st Ave, Maywood, IL, 60153, USA

    I. Caroline Le Poole, Cecele J. Denman & Tara M. Kroll

  2. Department of Gynecology and Obstetrics, Loyola University Medical Center, Maywood, IL, USA

    Wafic M. ElMasri

  3. Department of Microbiology and Immunology, Loyola University Medical Center, Maywood, IL, USA

    Hemamalini Bommiasamy

  4. Department of Surgery, University of Chicago, Chicago, IL, USA

    Gretchen Lyons Eiben

  5. Department of Molecular Microbiology and Immunology, Obstetrics and Gynecology, Norris Comprehensive Cancer Center, University of Southern California, Los Angeles, CA, USA

    W. Martin Kast

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  1. I. Caroline Le Poole
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  2. Wafic M. ElMasri
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  3. Cecele J. Denman
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  6. Gretchen Lyons Eiben
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Correspondence to I. Caroline Le Poole.

Additional information

I. Caroline Le Poole and W.M. ElMasri have contributed equally to this paper.

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Le Poole, I.C., ElMasri, W.M., Denman, C.J. et al. Langerhans cells and dendritic cells are cytotoxic towards HPV16 E6 and E7 expressing target cells. Cancer Immunol Immunother 57, 789–797 (2008). https://doi.org/10.1007/s00262-007-0415-z

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  • DOI: https://doi.org/10.1007/s00262-007-0415-z

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