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.

Targeting the CD47-SIRPα Innate Immune Checkpoint to Potentiate Antibody Therapy in Cancer by Neutrophils

“…In addition, there is accumulating evidence that also adaptive T cell-mediated anti-cancer immunity can be promoted by CD47-SIRPα blockade [ 183 , 184 ]. Clearly, this also sets the stage for a combination of CD47-SIRPα antagonists with PD1–PDL1 inhibitors [ 185 , 186 , 187 , 188 ]. Along these lines, there is even initial evidence that CAR-T cell activity may be promoted by CD47-SIRPα inhibitors [ 189 ].…”

Enhancing anti-tumour innate immunity by targeting the DNA damage response and pattern recognition receptors in combination with radiotherapy

“…PD-L1 (programmed death-ligand 1) expression is found to be elevated on tumour cells following irradiation due to interferon gamma (IFN-γ) release from tumour-infiltrating lymphocytes (TILs) ( 42 ) and TILs have increased expression of PD-1 (programmed death-1) following ex-vivo irradiation ( 43 ). A recent publication found that irradiation of colorectal cancer cells triggered an ATR-mediated DNA repair signalling pathway to upregulate CD47 and PD-L1, through engagement of signal-regulator protein α (SIRPα) and PD-1, respectively, to limit tumour-associated cross-presentation and suppression of innate immune activation ( 44 ).…”

Natural cell based biomimetic cellular transformers for targeted therapy of digestive system cancer

“…Tumor cells evade killing by the immune system by downregulating the expression of strong rejection antigens, downregulating major histocompatibility antigen I (MHC-I) levels, and impairing antigen-presenting function 190 . Utilizing semi biological hybrid cellular transforms to deliver drugs specifically to tumor cells, and induce specific types of cell death, would lead to the release of tumor associated antigens (TAAs), which in turn be recognized by immune cells and activate antitumor immune responses 191 .…”