Induction of Immunogenic Cell Death by Radiation-Upregulated Karyopherin Alpha 2 in Vitro

Eur J Cell Biol. Jun-Jul 2016;95(6-7):219-27. doi: 10.1016/j.ejcb.2016.04.002. Epub 2016 Apr 11.

Abstract

Accumulating evidence suggests the potential for radiation therapy to generate antitumor immune responses against tumor cells by inducing immunogenic cell death and phenotypic changes. We recently found that ionizing radiation upregulated karyopherin α2 (KPNA2) in HT-29 colorectal tumor cells using quantitative proteomic analysis. To determine whether this increased KPNA2 could function as a damage-associated molecular pattern to induce antitumor immune responses, mouse bone-marrow-derived dendritic cells (BMDCs) were treated with KPNA2. KPNA2 enhanced the surface expression of CD40, CD54, CD80, CD86, and MHC class I/II on BMDCs. DCs treated with KPNA2 exhibited increased secretion of pro-inflammatory cytokines such as IL-1β, IL-6, IL-12, IL-23, and TNF-α. Co-culture of CD4(+) T cells and KPNA2-treated DCs resulted in induction of Th1/17 cytokines (IFN-γ and IL-17) and reduction of TGF-β production. Moreover, KPNA2-treated DCs were capable of increasing granzyme B and perforin expression in cytotoxic T lymphocytes. These results demonstrated that radiation-induced dying colorectal cancer cells released considerable amounts of KPNA2 that induce the maturation and activation of DCs for synergistic antitumor effect of radiation.

Keywords: Danger signals; Dendritic cells; Immunogenic cell death; Ionizing radiation; Karyopherin α2.

MeSH terms

  • Animals
  • Cell Death / physiology
  • Cell Death / radiation effects
  • Cell Differentiation / physiology
  • Cell Differentiation / radiation effects
  • Cell Proliferation / physiology
  • Cell Proliferation / radiation effects
  • Colorectal Neoplasms / immunology*
  • Colorectal Neoplasms / pathology
  • Colorectal Neoplasms / radiotherapy*
  • Dendritic Cells / immunology*
  • Dendritic Cells / radiation effects
  • Female
  • HT29 Cells
  • Humans
  • Mice
  • Mice, Inbred BALB C
  • Nuclear Proteins / immunology*
  • Nuclear Proteins / metabolism
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / radiation effects
  • Up-Regulation / radiation effects
  • alpha Karyopherins / immunology*
  • alpha Karyopherins / metabolism

Substances

  • KPNA2 protein, human
  • Kpna2 protein, mouse
  • Nuclear Proteins
  • alpha Karyopherins