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

Available for download on Saturday, April 29, 2023

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