Author ORCID Identifier
0000-0002-2038-4537
Date of Graduation
5-2022
Document Type
Dissertation (PhD)
Program Affiliation
Cancer Biology
Degree Name
Doctor of Philosophy (PhD)
Advisor/Committee Chair
Michael A. Curran
Committee Member
Sunil Krishnan
Committee Member
Ronald A. DePinho
Committee Member
Steven H. Lin
Committee Member
Matthew M. Gubin
Committee Member
Eduardo Vilar-Sanchez
Abstract
Radiotherapy of colorectal cancer (CRC) can prime adaptive immunity against tumor-associated antigen (TAA)-expressing CRC cells systemically. However, incidences of abscopal tumor remission are extremely rare, and the post-irradiation immune escape mechanisms in CRC remain elusive. We report that CRC cells utilize a common DNA repair signaling pathway — ATR/Chk1/STAT3 — to upregulate both CD47 and PD-L1 in response to radiotherapy, which through engagement of SIRPα and PD-1 suppresses the capacity of antigen-presenting cells to phagocytose them thereby preventing TAA cross-presentation and innate immune activation. This post-irradiation CD47 and PD-L1 upregulation can be observed across various human solid tumor cells. Concordantly, rectal cancer patients with poor responses to neoadjuvant radiotherapy exhibited significantly elevated post-irradiation CD47 levels. The combination of radiotherapy, αSIRPα, and αPD-1 (RSP) reverses adaptive immune resistance and drives 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 RSP in both irradiated and abscopal tumors and prolonged survival in three distinct murine CRC models, including a cecal orthotopic model. In murine CRC, αSIRPα exerts superior tumoricidal efficacy versus αCD47 in combination with radiotherapy and αPD-1. We find RSP efficacy to be highly STING dependent as knockout animals lose most benefit of phagocytosis checkpoint blockade. Despite activation across the myeloid stroma, enhanced dendritic cell function accounts for most improvements in CD8 T cell priming. These data suggest ATR-mediated CD47 and PD-L1 upregulation as a key mechanism restraining radiation-induced immune priming in CRC. Blockade of the phagocytosis checkpoints SIRPα and PD-1 during radiotherapy promotes vigorous anti-tumor immune priming leading to systemic tumor regressions.
Keywords
radiotherapy, abscopal effect, CD47, SIRPα, PD-L1, PD-1, phagocytosis checkpoint, antigen cross-presentation, in situ tumor vaccination
Included in
Gastroenterology Commons, Immunity Commons, Immunotherapy Commons, Medical Immunology Commons, Oncology Commons, Radiation Medicine Commons
Comments
This was published in Science Immunology in June 2022. https://www.science.org/doi/10.1126/sciimmunol.abl9330
doi: 10.1126/sciimmunol.abl9330
Also available in PubMed Central: https://pubmed.ncbi.nlm.nih.gov/35687697/