ROS-induced autophagy in cancer cells assists in evasion from determinants of immunogenic cell death

Autophagy. 2013 Sep;9(9):1292-307. doi: 10.4161/auto.25399. Epub 2013 Jun 19.

Abstract

Calreticulin surface exposure (ecto-CALR), ATP secretion, maturation of dendritic cells (DCs) and stimulation of T cells are prerequisites for anticancer therapy-induced immunogenic cell death (ICD). Recent evidence suggests that chemotherapy-induced autophagy may positively regulate ICD by favoring ATP secretion. We have recently shown that reactive oxygen species (ROS)-based endoplasmic reticulum (ER) stress triggered by hypericin-mediated photodynamic therapy (Hyp-PDT) induces bona fide ICD. However, whether Hyp-PDT-induced autophagy regulates ICD was not explored. Here we showed that, in contrast to expectations, reducing autophagy (by ATG5 knockdown) in cancer cells did not alter ATP secretion after Hyp-PDT. Autophagy-attenuated cancer cells displayed enhanced ecto-CALR induction following Hyp-PDT, which strongly correlated with their inability to clear oxidatively damaged proteins. Furthermore, autophagy-attenuation in Hyp-PDT-treated cancer cells increased their ability to induce DC maturation, IL6 production and proliferation of CD4(+) or CD8(+) T cells, which was accompanied by IFNG production. Thus, our study unravels a role for ROS-induced autophagy in weakening functional interaction between dying cancer cells and the immune system thereby helping in evasion from ICD prerequisites or determinants.

Keywords: ATP; T cells; autophagy; calreticulin; cancer; dendritic cells; immunogenic cell death; photodynamic therapy (PDT).

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenosine Triphosphate / metabolism
  • Autophagy / drug effects*
  • Autophagy / immunology*
  • Autophagy-Related Protein 5
  • CD4-Positive T-Lymphocytes / cytology
  • CD4-Positive T-Lymphocytes / drug effects
  • CD8-Positive T-Lymphocytes / cytology
  • CD8-Positive T-Lymphocytes / drug effects
  • Calreticulin / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Dendritic Cells / drug effects
  • Dendritic Cells / metabolism
  • Gene Knockdown Techniques
  • Glutathione Peroxidase / metabolism
  • Histidine / pharmacology
  • Humans
  • Interferon-gamma / biosynthesis
  • Interleukin-6 / biosynthesis
  • Microtubule-Associated Proteins / metabolism
  • Models, Biological
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / pathology*
  • Oxidation-Reduction / drug effects
  • Perylene / analogs & derivatives
  • Perylene / pharmacology
  • Perylene / therapeutic use
  • Phenotype
  • Photochemotherapy
  • Reactive Oxygen Species / pharmacology*

Substances

  • ATG5 protein, human
  • Autophagy-Related Protein 5
  • Calreticulin
  • Interleukin-6
  • Microtubule-Associated Proteins
  • Reactive Oxygen Species
  • Histidine
  • Perylene
  • hypericin
  • Interferon-gamma
  • Adenosine Triphosphate
  • Glutathione Peroxidase