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.
Author Info: (1) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical
Author Info: (1) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan. (2) Department of Radiation Oncology, Mayo Clinic Florida, Jacksonville, FL, USA. (3) Department of Pathology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan. (4) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (5) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (6) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (7) University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (8) University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (9) Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan. (10) Department of Molecular and Cellular Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (11) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (12) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (13) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (14) Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan. (15) University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (16) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Parker Institute for Cancer Immunotherapy, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (17) University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Gastrointestinal Medical Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Clinical Cancer Prevention, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (18) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Neurology, Houston Methodist Neurological Institute, Houston Methodist Hospital, Houston, TX, USA. (19) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (20) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (21) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (22) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (23) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (24) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (25) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (26) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (27) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (28) Department of Radiation Oncology, Chang Gung Memorial Hospital at Linkou and Chang Gung University, Taoyuan, Taiwan. (29) Department of Radiation Oncology, Loyola University Stritch School of Medicine, Chicago, IL, USA. (30) University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (31) Department of Neurosurgery, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (32) University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. Department of Experimental Radiation Oncology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. (33) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA. (34) Department of Immunology, University of Texas MD Anderson Cancer Center, Houston, TX, USA. University of Texas MD Anderson Cancer Center UTHealth Graduate School of Biomedical Sciences, University of Texas Health Science Center at Houston, Houston, TX, USA.
