免疫系统
癌症研究
胰腺癌
免疫疗法
CD8型
先天免疫系统
癌症
T细胞
医学
免疫学
生物
内科学
作者
Qiang Zhang,Long Jiang,Weiwei Wang,Amanda K. Huber,Victoria M. Valvo,Kassidy M. Jungles,Erin A. Holcomb,Ashley N. Pearson,Stephanie The,Zhuwen Wang,Leslie A. Parsels,Joshua D. Parsels,Daniel R. Wahl,Arvind Rao,Vaibhav Sahai,Theodore S. Lawrence,Michael D. Green,Meredith A. Morgan
出处
期刊:JCI insight
[American Society for Clinical Investigation]
日期:2024-02-20
标识
DOI:10.1172/jci.insight.168824
摘要
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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