Radiation Induced Upregulation of DNA Sensing Pathways is Cell-Type Dependent and Can Mediate the Off-Target Effects

Cancers
Tanja JesenkoMaja Cemazar

Abstract

Irradiation of tumors generates danger signals and inflammatory cytokines that promote the off-target bystander and abscopal effects, evident especially when radiotherapy is administered in combination with the immune checkpoint inhibitors (ICI). The underlying mechanisms are not fully understood; however, cGAS-STING pathway was recognized as the main mediator. In our study, we demonstrate by immunofluorescent staining that tumor cells as well as macrophages, cell types abundant in the tumor microenvironmeent (TME) accumulate DNA in their cytosol soon after irradiation. This accumulation activated several distinct DNA sensing pathways, most prominently activated DNA sensors being DDX60, DAI, and p204 in tumor cells and DDX60, DAI, p204, and RIG-I in macrophages as determined by PCR and immunofluorescence imaging studies. This was accompanied by increased expression of cytokines evaluated by flow cytometry, TNFα, and IFNβ in tumor cells and IL1β and IFNβ in macrophages, which can alter the TME and mediate off-target effects (bystander or abscopal effects). These results give insight into the mechanisms involved in the stimulation of antitumor immunity by radiation.

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Citations

Feb 6, 2021·Journal of Clinical Medicine·Erika Huijser, Marjan A Versnel
Oct 20, 2021·Physics in Medicine and Biology·Paul CahoonStephen J McMahon

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Methods Mentioned

BETA
nuclear translocation
flow cytometry
electrophoresis
biopsies
scraping
X-Ray
PCR
transfection
Assay

Software Mentioned

GraphPad Prism
Fiji
ImageJ
Imaris

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