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Adenoviral-transduced dendritic cells are susceptible to suppression by T regulatory cells and promote interleukin 17 production

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Cancer Immunology, Immunotherapy Aims and scope Submit manuscript

Abstract

Dendritic cell (DC) vaccines offer a robust platform for the development of cancer vaccines, but their effectiveness is thought to be limited by T regulatory cells (Tregs). Recombinant adenoviruses (RAdV) have been used successfully to engineer tumor antigen expression in DCs, but the impact of virus transduction on susceptibility to suppression by Tregs is unknown. We investigated the functional consequences of exposure to adenovirus on interactions between human monocyte-derived DCs and Tregs. Since the development of Tregs is linked to that of pro-inflammatory Th17 cells, the role of Th17 cells and IL-17-producing Tregs in the context of DC-based immunotherapies was also investigated. We found that Tregs potently suppressed the co-stimulatory capacity of RAdV-transduced DCs, regardless of whether the DCs were maturated by inflammatory cytokines or by exposure to Th1 or Th17 cells. Furthermore, exposure of Tregs to RAdV-exposed DCs increased IL-17 production and suppressive capacity, and correlated with enhanced secretion of IL-1β and IL-6 by DCs. The findings that DCs exposed to RAdV are suppressed by Tregs, promote Treg plasticity, and enhance Treg suppression indicates that strategies to limit Tregs will be required to enhance the efficacy of such DC-based immunotherapies.

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Acknowledgments

This work was supported by a Terry Fox Foundation program project grant in cancer immunotherapy awarded to MKL, JAM and JLB. MKL holds a Canada Research Chair in Transplantation. AYW holds a CIHR Canada Graduate Award and a CIHR/SRTC Strategic Training Program in Transplantation award. SQC holds a MSFHR Senior Graduate Studentship award and CIHR/SRTC Strategic Training Programs in Skin and Transplantation awards. Core support for flow cytometry sorting provided by Lixin Xu and was funded by the Immunity and Infection Research Centre MSFHR Research Unit.

Conflict of interest

The authors declare no competing financial interests.

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Authors and Affiliations

  1. Department of Surgery, Immunity and Infection Research Centre, Vancouver Coastal Health Research Institute, University of British Columbia, 950 West 28th Ave, Vancouver, BC, V5Z4H4, Canada

    Adele Y. Wang, Sarah Q. Crome & Megan K. Levings

  2. Department of Pathology and Molecular Medicine Centre for Gene Therapeutics, McMaster University, Hamilton, ON, Canada

    Kristina M. Jenkins & Jonathan L. Bramson

  3. Ontario Cancer Institute, University Health Network, Toronto, ON, Canada

    Jeffrey A. Medin

Authors
  1. Adele Y. Wang
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  2. Sarah Q. Crome
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  3. Kristina M. Jenkins
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  4. Jeffrey A. Medin
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  5. Jonathan L. Bramson
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  6. Megan K. Levings
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Corresponding author

Correspondence to Megan K. Levings.

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Wang, A.Y., Crome, S.Q., Jenkins, K.M. et al. Adenoviral-transduced dendritic cells are susceptible to suppression by T regulatory cells and promote interleukin 17 production. Cancer Immunol Immunother 60, 381–388 (2011). https://doi.org/10.1007/s00262-010-0948-4

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  • DOI: https://doi.org/10.1007/s00262-010-0948-4

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