biostudies-literatureHsieh RCNCI NIH HHSeabl9330https://www.ebi.ac.uk/biostudies/studies/S-EPMC9373855biostudies-literatureUnknown7(72)Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirradScience immunologyATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer.PMC9373855P30 CA016672R01 CA231360Prasad RKim YSBDe Azevedo RAJayaprakash PLin SHSrinivasamani AChou YCBoda ARRudqvist NPBhanu KRVenkatesulu BPDePinho RAHsieh RCMorrow BTaniguchi CHsu WHSlay RChen JChan LCHartley GVilar EWu RCChen CHKrishnan SGubin MHegde SMWinkler MHung MCLea STLiu ASteiner MCouillault CAWang CCCurran MAfalseATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer.Radiotherapy (RT) of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, abscopal tumor remissions are extremely rare, and the postirradiation immune escape mechanisms in CRC remain elusive. Here, we found that irradiated CRC cells used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 and PD-L1, which through engagement of SIRPα and PD-1, respectively, prevented phagocytosis by antigen-presenting cells and thereby limited TAA cross-presentation and innate immune activation. This postirradiation CD47 and PD-L1 up-regulation was observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant RT exhibited significantly elevated postirrad2022-01-01T00:00:00Z2022 Jun2025-04-21T22:26:37.998Z2025-04-05T18:45:15.584ZS-EPMC93738553568769710.1126/sciimmunol.abl9330