Radiation fosters dose-dependent and chemotherapy-induced immunogenic cell death

作者：Encouse B. Golden, Derek Frances, Ilenia Pellicciotta, Sandra Demaria, Mary Helen Barcellos‐Hoff, Silvia C. Formenti · 发表于：OncoImmunology · 年份：2014 · DOI：10.4161/onci.28518 · 被引用次数：617 · 研究领域：Cancer Immunotherapy and Biomarkers、Immunotherapy and Immune Responses、Phagocytosis and Immune Regulation

Established tumors are typified by an immunosuppresive microenvironment. Countering this naturally occurring phenomenon, emerging evidence suggests that radiation promotes a proimmunogenic milieu within the tumor capable of stimulating host cancer-specific immune responses. Three cryptic immunogenic components of cytotoxic-agent induced cell death-namely, calreticulin cell surface exposure, the release of high mobility group box 1 (HMGB1) protein, and the liberation of ATP-have been previously shown to be critical for dendritic cell (DC) activation and effector T-cell priming. Thus, these immune-mobilizing components commonly presage tumor rejection in response to treatment. We initially set out to address the hypothesis that radiation-induced immunogenic cell death (ICD) is dose-dependent. Next, we hypothesized that radiation would enhance chemotherapy-induced ICD when given concomitantly, as suggested by the favorable clinical outcomes observed in response to analogous concurrent chemoradiation regimens. Thus, we designed an in vitro assay to examine the 3 hallmark features of ICD at clinically relevant doses of radiation. We then tested the immunogenic-death inducing effects of radiation combined with carboplatin or paclitaxel, focusing on these combinations to mimic chemoradiation regimens actually used in clinical trials of early stage triple negative [NCT0128953/NYU-10-01969] and locally advanced [NYU-06209] breast cancer patients, respectively. Despite the obvious limi...