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
Date
02/01/2014Pubmed ID
24480782Pubmed Central ID
PMC3964216DOI
10.18632/oncotarget.1719Scopus ID
2-s2.0-84896724517 (requires institutional sign-in at Scopus site) 314 CitationsAbstract
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.
Author List
Gameiro SR, Jammeh ML, Wattenberg MM, Tsang KY, Ferrone S, Hodge JWAuthor
Momodou L. Jammeh MD Assistant Professor in the Surgery department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Amino Acid SequenceAntigen Presentation
Breast Neoplasms
Calreticulin
Cell Line, Tumor
Dose-Response Relationship, Radiation
Endoplasmic Reticulum Stress
Female
Humans
Immunogenetics
Lung Neoplasms
Male
Molecular Sequence Data
Neoplasms
Prostatic Neoplasms
T-Lymphocytes, Cytotoxic
