High hydrostatic pressure induces immunogenic cell death in human tumor cells

Int J Cancer. 2014 Sep 1;135(5):1165-77. doi: 10.1002/ijc.28766. Epub 2014 Feb 20.


Recent studies have identified molecular events characteristic of immunogenic cell death (ICD), including surface exposure of calreticulin (CRT), the heat shock proteins HSP70 and HSP90, the release of high-mobility group box protein 1 (HMGB1) and the release of ATP from dying cells. We investigated the potential of high hydrostatic pressure (HHP) to induce ICD in human tumor cells. HHP induced the rapid expression of HSP70, HSP90 and CRT on the cell surface. HHP also induced the release of HMGB1 and ATP. The interaction of dendritic cells (DCs) with HHP-treated tumor cells led to a more rapid rate of DC phagocytosis, upregulation of CD83, CD86 and HLA-DR and the release of interleukin IL-6, IL-12p70 and TNF-α. DCs pulsed with tumor cells killed by HHP induced high numbers of tumor-specific T cells. DCs pulsed with HHP-treated tumor cells also induced the lowest number of regulatory T cells. In addition, we found that the key features of the endoplasmic reticulum stress-mediated apoptotic pathway, such as reactive oxygen species production, phosphorylation of the translation initiation factor eIF2α and activation of caspase-8, were activated by HHP treatment. Therefore, HHP acts as a reliable and potent inducer of ICD in human tumor cells.

Keywords: cancer immunotherapy; dendritic cells; heat shock proteins; high hydrostatic pressure; immunogenic cell death.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Antigens, CD / biosynthesis
  • Apoptosis / immunology*
  • B7-2 Antigen / biosynthesis
  • Calreticulin / biosynthesis
  • Calreticulin / immunology
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Dendritic Cells / immunology*
  • Endoplasmic Reticulum Stress / immunology
  • Enzyme Activation / immunology
  • Eukaryotic Initiation Factor-2 / metabolism
  • HLA-DR Antigens / biosynthesis
  • HMGB1 Protein / immunology
  • HMGB1 Protein / metabolism
  • HSP70 Heat-Shock Proteins / biosynthesis
  • HSP70 Heat-Shock Proteins / immunology
  • HSP90 Heat-Shock Proteins / biosynthesis
  • HSP90 Heat-Shock Proteins / immunology
  • Humans
  • Hydrostatic Pressure
  • Immunoglobulins / biosynthesis
  • Interleukin-12 / metabolism
  • Interleukin-6 / metabolism
  • Membrane Glycoproteins / biosynthesis
  • Membrane Proteins / biosynthesis
  • Neoplasms / immunology*
  • Phagocytosis / immunology
  • Phosphorylation
  • Reactive Oxygen Species / metabolism
  • T-Lymphocytes, Regulatory / immunology*
  • Tumor Necrosis Factor-alpha / metabolism


  • Antigens, CD
  • B7-2 Antigen
  • CD83 antigen
  • CD86 protein, human
  • Calreticulin
  • Eukaryotic Initiation Factor-2
  • HLA-DR Antigens
  • HMGB1 Protein
  • HMGB1 protein, human
  • HSP70 Heat-Shock Proteins
  • HSP90 Heat-Shock Proteins
  • IL6 protein, human
  • Immunoglobulins
  • Interleukin-6
  • Membrane Glycoproteins
  • Membrane Proteins
  • Reactive Oxygen Species
  • Tumor Necrosis Factor-alpha
  • Interleukin-12
  • Adenosine Triphosphate
  • Caspase 8