Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy

Paul Hatfield, Alison E. Merrick, Emma West, Dearbhaile O'Donnell, Peter Selby, Richard Geoffrey Vile, Alan A. Melcher

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

The immune response to cancer is critically determined by the way in which tumor cells die. As necrotic, stressassociated death can be associated with activation of antitumor immunity, whole tumor cell antigen loading strategies for dendritic cell (DC)-based vaccination have commonly used freeze-thaw "necrotic" lysates as an immunogenic source of tumor-associated antigens. In this study, the effect of such lysates on the ability of DCs to mature in response to wellestablished maturation stimuli was examined, and methods to enhance lysate-induced DC activation explored. Freeze-thaw lysates were prepared from murine tumor cell lines and their effects on bone marrow-derived DC maturation and function examined. Unmodified freeze-thaw tumor cell lysates inhibited the toll-like receptor-induced maturation and function of bone marrow-derived DCs, preventing up-regulation of CD40, CD86, and major histocompatibility complex class II, and reducing secretion of inflammatory cytokines [interleukin (IL)-12 p70, tumor necrosis factor-α, and IL-6]. Although IL-10 secretion was increased by lysate-pulsed DCs, this was not responsible for the observed suppression of IL-12. Although activation of the nuclear factor-kB pathway remained intact, the kinase activity of phosphorylated p38 mitogen-activated protein kinase was inhibited in lysate-pulsed DCs. Lysate-induced DC suppression was partially reversed in vitro by induction of tumor cell stress before lysis, and only DCs loaded with stressed lysates afforded protection against tumor challenge in vivo. These data suggest that ex vivo freeze-thaw of tumor cells does not effectively mimic in vivo immunogenic necrosis, and advocates careful characterization and optimization of tumor cell-derived vaccine sources for cancer immunotherapy.

Original languageEnglish (US)
Pages (from-to)620-632
Number of pages13
JournalJournal of Immunotherapy
Volume31
Issue number7
DOIs
StatePublished - Sep 2008

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Immunotherapy
Dendritic Cells
Neoplasms
Neoplasm Antigens
Interleukin-12
Bone Marrow
Cancer Vaccines
Toll-Like Receptors
p38 Mitogen-Activated Protein Kinases
Tumor Cell Line
Major Histocompatibility Complex
Interleukin-10
Immunity
Interleukin-6
Vaccination
Necrosis
Phosphotransferases
Up-Regulation
Tumor Necrosis Factor-alpha
Cytokines

Keywords

  • Dendritic cell
  • Lysate
  • Maturation
  • Necrosis
  • TLR

ASJC Scopus subject areas

  • Immunology
  • Immunology and Allergy
  • Cancer Research
  • Pharmacology
  • Medicine(all)

Cite this

Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy. / Hatfield, Paul; Merrick, Alison E.; West, Emma; O'Donnell, Dearbhaile; Selby, Peter; Vile, Richard Geoffrey; Melcher, Alan A.

In: Journal of Immunotherapy, Vol. 31, No. 7, 09.2008, p. 620-632.

Research output: Contribution to journalArticle

Hatfield, P, Merrick, AE, West, E, O'Donnell, D, Selby, P, Vile, RG & Melcher, AA 2008, 'Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy', Journal of Immunotherapy, vol. 31, no. 7, pp. 620-632. https://doi.org/10.1097/CJI.0b013e31818213df
Hatfield, Paul ; Merrick, Alison E. ; West, Emma ; O'Donnell, Dearbhaile ; Selby, Peter ; Vile, Richard Geoffrey ; Melcher, Alan A. / Optimization of dendritic cell loading with tumor cell lysates for cancer immunotherapy. In: Journal of Immunotherapy. 2008 ; Vol. 31, No. 7. pp. 620-632.
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