Article ; Online: Potentiating the radiation-induced type I interferon antitumoral immune response by ATM inhibition in pancreatic cancer.
JCI insight
2024 Volume 9, Issue 6
Abstract: Radiotherapy induces a type I interferon-mediated (T1IFN-mediated) antitumoral immune response that we hypothesized could be potentiated by a first-in-class ataxia telangiectasia mutated (ATM) inhibitor, leading to enhanced innate immune signaling, T1IFN ...
| Abstract | Radiotherapy induces a type I interferon-mediated (T1IFN-mediated) antitumoral immune response that we hypothesized could be potentiated by a first-in-class ataxia telangiectasia mutated (ATM) inhibitor, leading to enhanced innate immune signaling, T1IFN expression, and sensitization to immunotherapy in pancreatic cancer. We evaluated the effects of AZD1390 or a structurally related compound, AZD0156, on innate immune signaling and found that both inhibitors enhanced radiation-induced T1IFN expression via the POLIII/RIG-I/MAVS pathway. In immunocompetent syngeneic mouse models of pancreatic cancer, ATM inhibitor enhanced radiation-induced antitumoral immune responses and sensitized tumors to anti-PD-L1, producing immunogenic memory and durable tumor control. Therapeutic responses were associated with increased intratumoral CD8+ T cell frequency and effector function. Tumor control was dependent on CD8+ T cells, as therapeutic efficacy was blunted in CD8+ T cell-depleted mice. Adaptive immune responses to combination therapy provided systemic control of contralateral tumors outside of the radiation field. Taken together, we show that a clinical candidate ATM inhibitor enhances radiation-induced T1IFN, leading to both innate and subsequent adaptive antitumoral immune responses and sensitization of otherwise resistant pancreatic cancer to immunotherapy. |
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| MeSH term(s) | Animals ; Mice ; Interferon Type I ; Ataxia Telangiectasia ; Pancreatic Neoplasms/drug therapy ; Pancreatic Neoplasms/radiotherapy ; Pancreatic Neoplasms/pathology ; Immunity ; Pyridines ; Quinolones |
| Chemical Substances | Interferon Type I ; AZD1390 ; Pyridines ; Quinolones |
| Language | English |
| Publishing date | 2024-02-20 |
| Publishing country | United States |
| Document type | Journal Article |
| ISSN | 2379-3708 |
| ISSN (online) | 2379-3708 |
| DOI | 10.1172/jci.insight.168824 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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