The schedule of ATR inhibitor AZD6738 can potentiate or abolish antitumor immune responses to radiotherapy.
The schedule of ATR inhibitor AZD6738 can potentiate or abolish antitumor immune responses to radiotherapy.
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DOI：
10.1172/jci.insight.165615
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发表时间：
2023-02-22
期刊：
影响因子：
8
通讯作者：
Bakkenist, Christopher J.
中科院分区：
文献类型：
--
作者：
Vendetti, Frank P.;Pandya, Pinakin;Clump, David A.;Schamus-Haynes, Sandra;Tavakoli, Meysam;diMayorca, Maria;Islam, Naveed M.;Chang, Jina;Delgoffe, Greg M.;Beumer, Jan H.;Bakkenist, Christopher J.
DNA损伤信号激酶ATR抑制剂通过靶向DNA复制叉的化疗增加肿瘤细胞杀伤，但也杀死快速增殖的免疫细胞，包括活化的T细胞。然而，在小鼠模型中，ATR抑制剂（ATRi）和放疗（RT）可以联合产生CD8+ T细胞依赖的抗肿瘤反应。为了确定ATRi和RT的最佳时间表，我们确定了AZD6738 （ATRi）短期疗程与延长每日治疗对RT反应（1-2天）的影响。短期ATRi（1 - 3天）加RT可在RT后1周引起肿瘤引流淋巴结（DLN）中肿瘤抗原特异性、效应CD8+ T细胞的扩增。在此之前，ATRi停止后，肿瘤浸润性和外周性T细胞的增殖性急剧下降，增殖性反弹，肿瘤中炎症信号（IFN-β、趋化因子，特别是CXCL10）增加，DLN中炎症细胞积聚。相比之下，延长的ATRi（第1-9天）阻止了DLN中肿瘤抗原特异性、效应CD8+ T细胞的扩增，并完全抵消了短期ATRi与RT和抗pd - l1的治疗效果。我们的数据表明，停止ATRi对于允许CD8+ T细胞对RT和免疫检查点抑制剂产生应答至关重要。
Inhibitors of the DNA damage signaling kinase ATR increase tumor cell killing by chemotherapies that target DNA replication forks but also kill rapidly proliferating immune cells including activated T cells. Nevertheless, ATR inhibitor (ATRi) and radiotherapy (RT) can be combined to generate CD8+ T cell–dependent antitumor responses in mouse models. To determine the optimal schedule of ATRi and RT, we determined the impact of short-course versus prolonged daily treatment with AZD6738 (ATRi) on responses to RT (days 1–2). Short-course ATRi (days 1–3) plus RT caused expansion of tumor antigen–specific, effector CD8+ T cells in the tumor-draining lymph node (DLN) at 1 week after RT. This was preceded by acute decreases in proliferating tumor-infiltrating and peripheral T cells and a rapid proliferative rebound after ATRi cessation, increased inflammatory signaling (IFN-β, chemokines, particularly CXCL10) in tumors, and an accumulation of inflammatory cells in the DLN. In contrast, prolonged ATRi (days 1–9) prevented the expansion of tumor antigen–specific, effector CD8+ T cells in the DLN, and entirely abolished the therapeutic benefit of short-course ATRi with RT and anti–PD-L1. Our data argue that ATRi cessation is essential to allow CD8+ T cell responses to both RT and immune checkpoint inhibitors.
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影响因子：
11.2
作者：
Burnette BC;Liang H;Lee Y;Chlewicki L;Khodarev NN;Weichselbaum RR;Fu YX;Auh SL
通讯作者：
Auh SL
影响因子：
8
作者：
Fransen, Marieke F.;Schoonderwoerd, Mark;Ossendorp, Ferry
通讯作者：
Ossendorp, Ferry
影响因子：
7.3
作者：
Foote, Kevin M.;Nissink, J. Willem M.;Jewsbury, Philip J.
通讯作者：
Jewsbury, Philip J.
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
18.4
作者：
Böttcher JP;Reis e Sousa C
通讯作者：
Reis e Sousa C