Hsieh et al. showed CD47, the receptor for SIRPα – the don’t eat me signal – is upregulated on a variety of human solid tumor lines and rectal cancer biopsies, particularly from patients with poor responses to neoadjuvant radiotherapy (RT) and surgery. In vitro, RT of human CRC cells induced ATR-mediated DNA repair that led to CD47 and PD-L1 upregulation. In mouse CRC models, RT/anti-PD-1/anti-SIRPα treatment induced responses in irradiated s.c. and abscopal tumors to promote phagocytosis of tumor cells; DC/STING-dependent TAA-specific CD8+ T cell priming; and Teff cell activation, clonal expansion, and TCR diversity to extend host survival and induce memory.
Contributed by Paula Hochman
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.