ATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer

• DOI: 10.1126/sciimmunol.abl9330
• Publication Date: 2022-06-10T17:58:21Z
• Authors: Rodney Cheng-En H...; Sunil Krishnan; Ren-Chin Wu; Akash R. Boda; Arthur Liu; Michelle Winkler; Wen-Hao Hsu; Steven Hsesheng Lin; Mien-Chie Hung; Li-Chuan Chan; Krithikaa Rajkuma...; Anupallavi Sriniv...; Ricardo Alexandre...; Yung-Chih Chou; Ronald A. DePinho; Matthew Gubin; Eduardo Vilar; Chao Hsien Chen; Ravaen Slay; Priyamvada Jayapr...; Shweta Mahendra H...; Genevieve Hartley; Spencer T. Lea; Rishika Prasad; Brittany Morrow; Coline Agnes Coui...; Madeline Steiner; Chun-Chieh Wang; Bhanu Prasad Venk...; Cullen Taniguchi; Yon Son Betty Kim; Junjie Chen; Nils-Petter Rudqvist; Michael A. Curran
• Keywords: CD47; Priming (agriculture)

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 remain elusive. Here, we found that irradiated used ATR-mediated DNA repair signaling pathway to up-regulate both CD47 PD-L1, which through engagement SIRPα PD-1, respectively, prevented phagocytosis by antigen-presenting thereby limited TAA cross-presentation innate activation. This PD-L1 up-regulation was observed across various human solid cells. Concordantly, rectal patients with poor responses neoadjuvant RT exhibited significantly elevated levels. The combination RT, anti-SIRPα, anti-PD-1 reversed resistance drove efficient cross-presentation, resulting robust TAA-specific CD8 T cell priming, functional activation effectors, increased clonality clonal diversity. We higher complete response rates RT/anti-SIRPα/anti-PD-1 tumors prolonged survival three distinct murine models, including a cecal orthotopic model. efficacy triple therapy STING dependent as knockout animals lost most benefit adding anti-SIRPα RT. Despite myeloid stroma, enhanced dendritic function accounts for improvements priming. These data suggest key mechanism restraining radiation-induced combined PD-1 blockade promotes antitumor leading systemic regressions.