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  • Poster presentation
  • Open Access

Cross-presentation of the oncofoetal tumor antigen 5T4 from irradiated prostate cancer cells - a key role for Hsp70

  • 1,
  • 1,
  • 2,
  • 1,
  • 1,
  • 1 and
  • 1
Journal for ImmunoTherapy of Cancer20142 (Suppl 3) :P161

https://doi.org/10.1186/2051-1426-2-S3-P161

  • Published:

Keywords

  • Prostate Cancer
  • Dendritic Cell
  • Cell Stimulation
  • DU145 Cell
  • Hsp70 Inhibitor

Immune responses contribute to the success of radiation therapy of solid tumors; however, the mechanism of triggering CD8+ T cell responses is poorly understood. Antigen cross-presentation from tumor cells by dendritic cells (DC) is a likely dominant mechanism to achieve CD8+ T cell stimulation. We established a cross-presentation model in prostate cancer in which DC present a naturally expressed oncofoetal tumor antigen (5T4) from irradiated DU145 tumor cells to 5T4-specific T cells. Ionising radiation (12 Gy) caused G2/M cell cycle arrest and cell death, increased cellular 5T4 levels, induced passive release of high-mobility protein group-B1 (HMGB1) and upregulated surface calreticulin and Hsp70 expression in DU145 cells. Co-culture of DC with irradiated tumor cells lead to efficient phagocytosis of tumor cells and upregulation of CD86 and HLA-DR on DC. CD8+ 5T4-specific T cells, stimulated with these DC, proliferated and produced IFNγ. Inhibition of HMGB1 function decreased T cell stimulation but not DC activation, while TRIF/MyD88 inhibition only had a marginal effect on T cell stimulation. Unlike previous reports, we found no functional evidence that DC with Asp299Gly toll-like receptor-4 (TLR4) single nucleotide polymorphism had impaired ability to cross-present tumor antigen. However, we observed a highly significant and robust prevention of antigen cross-presentation when tumor cells were pre-treated with the novel Hsp70 inhibitor, VER155008. The inhibitor also prevented CD86 upregulation on DC co-cultured with irradiated tumor cells. Together, our study demonstrates that radiation induces immunologically relevant changes in tumor cells, which can trigger CD8+ T cell responses via a predominantly Hsp70-dependent antigen cross-presentation process.

Authors’ Affiliations

(1)
Cardiff University, Cardiff, UK
(2)
Velindre NHS Trust, Cardiff, UK

Copyright

© Salimu et al.; licensee BioMed Central Ltd. 2014

This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

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