Radiation-induced immunogenic modulation of tumor enhances antigen processing and calreticulin exposure, resulting in enhanced T-cell killing

Oncotarget. 2014 Jan 30;5(2):403-16. doi: 10.18632/oncotarget.1719.

Abstract

Radiation therapy (RT) is used for local tumor control through direct killing of tumor cells. Radiation-induced cell death can trigger tumor antigen-specific immune responses, but these are often noncurative. Radiation has been demonstrated to induce immunogenic modulation (IM) in various tumor types by altering the biology of surviving cells to render them more susceptible to T cell-mediated killing. Little is known about the mechanism(s) underlying IM elicited by sub-lethal radiation dosing. We have examined the molecular and immunogenic consequences of radiation exposure in breast, lung, and prostate human carcinoma cells. Radiation induced secretion of ATP and HMGB1 in both dying and surviving tumor cells. In vitro and in vivo tumor irradiation induced significant upregulation of multiple components of the antigen-processing machinery and calreticulin cell-surface expression. Augmented CTL lysis specific for several tumor-associated antigens was largely dictated by the presence of calreticulin on the surface of tumor cells and constituted an adaptive response to endoplasmic reticulum stress, mediated by activation of the unfolded protein response. This study provides evidence that radiation induces a continuum of immunogenic alterations in tumor biology, from immunogenic modulation to immunogenic cell death. We also expand the concept of immunogenic modulation, where surviving tumor cells recovering from radiation-induced endoplasmic reticulum stress become more sensitive to CTL killing. These observations offer a rationale for the combined use of radiation with immunotherapy, including for patients failing RT alone.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural

MeSH terms

  • Amino Acid Sequence
  • Antigen Presentation / drug effects
  • Antigen Presentation / radiation effects*
  • Breast Neoplasms / drug therapy
  • Breast Neoplasms / immunology
  • Breast Neoplasms / radiotherapy
  • Calreticulin / pharmacology*
  • Cell Line, Tumor
  • Dose-Response Relationship, Radiation
  • Endoplasmic Reticulum Stress / drug effects
  • Endoplasmic Reticulum Stress / immunology
  • Endoplasmic Reticulum Stress / radiation effects
  • Female
  • Humans
  • Immunogenetics
  • Lung Neoplasms / drug therapy
  • Lung Neoplasms / immunology
  • Lung Neoplasms / radiotherapy
  • Male
  • Molecular Sequence Data
  • Neoplasms / drug therapy
  • Neoplasms / immunology*
  • Neoplasms / radiotherapy*
  • Prostatic Neoplasms / drug therapy
  • Prostatic Neoplasms / immunology
  • Prostatic Neoplasms / radiotherapy
  • T-Lymphocytes, Cytotoxic / cytology
  • T-Lymphocytes, Cytotoxic / drug effects
  • T-Lymphocytes, Cytotoxic / immunology
  • T-Lymphocytes, Cytotoxic / radiation effects*

Substances

  • Calreticulin