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  • Open Access

Selective costimulation by IL-15R/IL-15, but not IL-2R/IL-2, allows the induction of high numbers of tumor-specific CD8+ T cells by human dendritic cells matured in conditions of acute inflammation

  • 1,
  • 2,
  • 3,
  • 2 and
  • 2
Journal for ImmunoTherapy of Cancer20153 (Suppl 2) :P223

https://doi.org/10.1186/2051-1426-3-S2-P223

  • Published:

Keywords

  • Malignant Melanoma
  • Dendritic Cell
  • Metastatic Malignant Melanoma
  • Tumor Rejection
  • Dendritic Cell Vaccine

Conventional dendritic cells (DC) are believed to rely on membrane-bound IL-2Rα to trans-present soluble IL-2 and costimulate T cell activation and expansion. In contrast, Langerhans cells have been shown to use membrane-bound IL-15Rα/IL-15 complex to activate T cells. Here we show that, while the expansion of tumor-specific CD8+ T cells by DC matured in the presence of chronic inflammatory mediators (PGE2, TNFα IL-1β, IL-6) fully depends on expression of IL-2Rα, CD8+ T cell expansion induced by IL-12p70-producing DC matured by interferon's and Toll-Like receptor ligands (type-1-polarized; DC1) is both more effective and independent of IL-2Rα expression. While DC1-expressed IL-15Rα promotes the expansion of tetramer-specific CD8+ T cells, their secreted levels of IL-12p70 determines the degree of CD8+ T cell functionality as evidenced by tumor antigen-specific release of IFNγ and TNFα. In accordance with the in vivo advantage of utilizing an IL-2-independent pathway of costimulation of tumor-specific T cells, in a retrospectively analyzed cohort of patients with metastatic malignant melanoma treated with cyclophosphamide and tumor-antigen transfected DCs (NCT00978913) we observed a highly significant inverse relation between overall survival and expression of IL-2Rα on DC vaccine products (p = 0.009). The differential usage of IL-2Rα/IL-2 versus IL-15Rα/IL-15 pathways by subsets of DCs helps to explain the role of different types of inflammation in memory formation, exhaustion of CD8+ T cell responses and progression of cancer. Furthermore, ex vivo induction of IL-15Rα/IL-15 dependent signaling might improve adoptive T cell therapies targeting tumors with well-defined and undefined tumor rejection antigens.

Authors’ Affiliations

(1)
Copenhagen University Hospital, Herlev, Denmark
(2)
University of Pittsburgh, Pittsburgh, PA, USA
(3)
Center for Cancer Immune Therapy, Herlev Hospital, Copenhagen University, Herlev, Denmark

Copyright

© Hansen et al. 2015

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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