DNA damage signaling to immune checkpoints

DNA 损伤向免疫检查点发出信号

基本信息

批准号：
10078939
负责人：
CHRISTOPHER J. BAKKENIST
金额：
$ 34.8万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-01-01 至 2022-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10078939
关键词：
Affinity Chromatography Antigen Presentation Attenuated Binding CD8-Positive T-Lymphocytes CT26 Cancer Model Cancer Patient Cell Cycle Checkpoint Cell surface Cells Chemicals Cisplatin Clinical Clinical Trials Network Colorectal Cancer Complex Conformal Radiotherapy Cytoplasm Cytotoxic T-Lymphocytes DNA DNA Damage DNA Repair Diagnosis Disease Progression Drug usage Effector Cell Endoplasmic Reticulum Fluorescence Recovery After Photobleaching Genetic Models Goals Histocompatibility Antigens Class I IRF1 gene Immobilization Immune Ionizing radiation KRASG12D Knock-out Ligands MC38 MHC Class I Genes Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Mass Spectrum Analysis Mus Mutation Non-Small-Cell Lung Carcinoma Nonmetastatic Nuclear Outcome Pathway interactions Patients Pharmacologic Substance Phase I Clinical Trials Phosphotransferases Protein Biosynthesis Proteins Proteomics Radiation Resected Signal Pathway Signal Transduction Structure T cell response T-Cell Depletion TP53 gene Tobacco-Associated Carcinogen Translations Up-Regulation Xenograft Model anti-PD-L1 anti-PD1 antibodies anti-PD1 therapy anti-tumor immune response antigenic peptide transporter ataxia telangiectasia mutated protein cancer cell cancer therapy curative treatments cytotoxic defined contribution experimental study immune checkpoint immune checkpoint blockade immune self tolerance kinase inhibitor lung cancer cell malignant breast neoplasm member mouse model neoplastic cell novel novel therapeutics patient derived xenograft model prevent programmed cell death ligand 1 programmed cell death protein 1 radiation response replication stress resistance mechanism response standard of care targeted treatment transcription factor tumor

项目摘要

Lung cancer is diagnosed late, has a 5 year survival of only 15%, and kills more people than colorectal, breast and prostate cancer combined. Less than 30% of lung cancers are resected and the majority of patients are treated with cisplatin and ionizing radiation (IR). We show that inhibition of DNA damage signaling by ATR kinase during treatment with cisplatin and IR is well-tolerated and leads to durable responses in mouse xenograft and genetic models of lung cancer. Quite unexpectedly, we show that in addition to potentiating DNA damage, two clinical ATR kinase inhibitors (ATRi’s), with unrelated structures, block expression of the immune checkpoint protein PD-L1 and increase presentation of MHC class I antigens in lung cancer cells after IR. Our finding that crosstalk exists between DNA damage signaling and immune checkpoints has not been described previously and is the focus of this proposal. Immune-inhibitory pathways, termed immune checkpoints, are coopted by tumor cells to evade cytotoxic immune cells. PD-1 is expressed on cytotoxic T cells and its ligand PD-L1 is upregulated in lung cancers. PD-L1 binding by PD-1 prevents the activation of cytotoxic T cells. Immune checkpoint blockade using anti-PD-L1 and anti-PD-1 antibodies restores anti-tumor immune responses and is emerging as an exciting lung cancer therapy. We propose that ATRi’s inhibit DNA repair and cell cycle checkpoints potentiating the DNA damage induced by cisplatin and IR while concurrently inhibiting PD-L1 expression and restoring anti-tumor immune responses. Our objective in this proposal is to define the mechanisms that connect DNA damage signaling and immune checkpoints. This objective will be accomplished by the following Specific Aims. Aim 1: To determine how ATRi’s inhibit PD-L1 expression in lung cancer cells after IR. This aim will define the contribution of ATR, ATM, IRF-1, NF-κB and p53 to PD-L1 expression after IR. Aim 2: To determine how ATRi’s increase MHC class I expression on lung cancer cells after IR. This aim will identify ATR, ATM, and p53 signaling that inhibits protein synthesis and MHC class I presentation after IR. Aim 3: To identify ATRi-induced PDL-1/PD-1 immune checkpoint blockade in lung cancer after IR. This aim will identify ATRi-induced immune checkpoint blockade in lung cancer after IR. The outcomes of these Aims will identify mechanisms that connect DNA damage signaling to immune self- tolerance. This will define a novel therapeutic opportunity to use ATRi’s to potentiate the DNA damage induced by cisplatin and IR while concurrently inducing immune checkpoint blockade.

肺癌诊断较晚，5年生存率仅为15%，并且比结直肠癌造成更多死亡，乳腺癌和前列腺癌加在一起，只有不到 30% 的肺癌被切除，而大多数则被切除。患者接受顺铂和电离辐射 (IR) 治疗，我们发现 DNA 损伤信号传导受到抑制。顺铂和 IR 治疗期间 ATR 激酶的作用具有良好的耐受性，并在小鼠中产生持久的反应出乎意料的是，我们发现肺癌的异种移植和遗传模型除了增强作用之外，还具有增强作用。 DNA 损伤，两种具有不相关结构的临床 ATR 激酶抑制剂 (ATRi’s) 会阻断 DNA 损伤的表达免疫检查点蛋白 PD-L1 并增加肺癌细胞中 MHC I 类抗原的呈递 IR。我们发现 DNA 损伤信号传导和免疫检查点之间存在串扰，但尚未得到证实。免疫抑制途径（称为免疫）是本提案的重点。检查点，被肿瘤细胞利用以逃避在细胞毒性 T 上表达的 PD-1。细胞及其配体 PD-L1 在肺癌中上调，PD-1 与 PD-L1 的结合可防止其激活。使用抗 PD-L1 和抗 PD-1 抗体阻断免疫检查点可恢复抗肿瘤作用。我们建议 ATRi 抑制 DNA，并正在成为一种令人兴奋的肺癌疗法。修复和细胞周期检查点同时增强顺铂和 IR 诱导的 DNA 损伤抑制 PD-L1 表达并恢复抗肿瘤免疫反应。定义连接 DNA 损伤信号和免疫检查点的机制。通过以下具体目标 1 来实现：确定 ATRi 如何抑制肺中的 PD-L1 表达。该目标将确定 ATR、ATM、IRF-1、NF-κB 和 p53 对 PD-L1 的贡献。目标 2：确定 ATRi 如何增加肺癌细胞上 MHC I 类的表达。 IR 之后，该目标将识别抑制蛋白质合成和 MHC I 类的 ATR、ATM 和 p53 信号传导。目标 3：确定 ATRi 诱导的肺癌中 PDL-1/PD-1 免疫检查点阻断。该目标将确定 IR 后肺癌中 ATRi 诱导的免疫检查点阻断。这些目标的结果将确定将 DNA 损伤信号传导与免疫自我连接联系起来的机制。这将为使用 ATRi 增强 DNA 损伤提供新的治疗机会。由顺铂和IR诱导，同时诱导免疫检查点阻断。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Dormant origin signaling during unperturbed replication.

不受干扰的复制过程中休眠的起源信号传导。

DOI：
10.1016/j.dnarep.2019.102655
发表时间：
2019
期刊：
DNA repair
影响因子：
3.8
作者：
Moiseeva,TatianaN;Bakkenist,ChristopherJ
通讯作者：
Bakkenist,ChristopherJ

RAD-ADAPT: Software for modelling clonogenic assay data in radiation biology.

DOI：
10.1016/j.dnarep.2017.02.004
发表时间：
2017-04
期刊：
DNA repair
影响因子：
3.8
作者：
Zhang Y;Hu K;Beumer JH;Bakkenist CJ;D'Argenio DZ
通讯作者：
D'Argenio DZ

ATR gene mutations in HPV negative oropharyngeal cancer.

HPV 阴性口咽癌中的 ATR 基因突变。

DOI：
10.1016/j.oraloncology.2016.12.009
发表时间：
2017
期刊：
Oral oncology
影响因子：
4.8
作者：
Jeannon,Jean-Pierre;Tanaka,Akio;Thavaraj,Selvam;Guerrero-Urbano,Teresa;McGrath,JohnA;Tavassoli,Mahvash
通讯作者：
Tavassoli,Mahvash

Regulation of the initiation of DNA replication in human cells.

DOI：
10.1016/j.dnarep.2018.09.003
发表时间：
2018-12
期刊：
DNA repair
影响因子：
3.8
作者：
Moiseeva TN;Bakkenist CJ
通讯作者：
Bakkenist CJ

Radiopotentiation Profiling of Multiple Inhibitors of the DNA Damage Response for Early Clinical Development.

DOI：
10.1158/1535-7163.mct-20-0502
发表时间：
2021-09
期刊：
Molecular cancer therapeutics
影响因子：
5.7
作者：
Gill SJ;Wijnhoven PWG;Fok JHL;Lloyd RL;Cairns J;Armenia J;Nikkilä J;Lau A;Bakkenist CJ;Galbraith SM;Vens C;O'Connor MJ
通讯作者：
O'Connor MJ