ATR-mediated CD47 and PD-L1 up-regulation restricts radiotherapy-induced immune priming and abscopal responses in colorectal cancer
Cheng‐En Hsieh, Sunil Krishnan, Ren‐Chin Wu, Akash R. Boda, Arthur Liu, Michelle Winkler, Wen‐Hao Hsu, Steven H. Lin, Mien‐Chie Hung, Li-Chuan Chan, Krithikaa Rajkumar Bhanu, Anupallavi Srinivasamani, Ricardo Azevedo, Yung‐Chih Chou, Ronald A. DePinho, Matthew M. Gubin, Eduardo Vilar, Chao-Hsien Chen, Ravaen Slay, Priyamvada Jayaprakash, Shweta Hegde, Genevieve Hartley, Spencer T. Lea, Rishika Prasad, Brittany Morrow, Coline Couillault, Madeline Steiner, Chun‐Chieh Wang, Bhanu Prasad Venkatesulu, Cullen M. Taniguchi, Betty Y.S. Kim, Junjie Chen, Nils-Petter Rudqvist, Michael A. Curran
Abstract
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 postirradiation CD47 levels. The combination of RT, anti-SIRPα, and anti-PD-1 reversed adaptive immune resistance and drove efficient TAA cross-presentation, resulting in robust TAA-specific CD8 T cell priming, functional activation of T effectors, and increased T cell clonality and clonal diversity. We observed significantly higher complete response rates to RT/anti-SIRPα/anti-PD-1 in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. The efficacy of triple combination therapy was STING dependent as knockout animals lost most benefit of adding anti-SIRPα and anti-PD-1 to RT. Despite activation across the myeloid stroma, the enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 up-regulation as a key mechanism restraining radiation-induced immune priming. RT combined with SIRPα and PD-1 blockade promotes robust antitumor immune priming, leading to systemic tumor regressions.