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

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.

Abstract

ATR signaling up-regulates CD47 and PD-L1 in irradiated CRC cells, preventing phagocytosis and tumor antigen cross-presentation by APCs.

Engulfing to improve radiation

Despite the wide use of radiation therapy (RT) in colorectal cancer, many patients experience progression at non-irradiated sites of disease. Thus, it is crucial to improve the abscopal effects of RT. Here, Hsieh et al. used mouse modeling and human cancer cell lines to show that RT increased the expression of CD47 and PD-L1 in a DNA repair signaling–dependent manner. Targeting CD47 and PD-L1 with anti-SIRPα and anti-PD-1, respectively, in combination with RT led to clearance of primary tumors and robust abscopal effects. This triple combination depended on host STING expression, leading to improved tumor cell phagocytosis and subsequent cross-priming of tumor antigen–specific T cells. Together, these data suggest that targeting immune checkpoints and phagocytosis during RT may help patients with colorectal cancer.