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.

肺癌被诊断出来，仅5年生存率仅为15％，而杀死的人数超过结直肠癌，乳腺癌和前列腺癌的合并。切除了不到30％的肺癌和大多数用顺铂和电离辐射（IR）治疗患者。我们表明抑制DNA损伤信号传导用顺铂和IR治疗期间ATR激酶的耐受性良好，并导致小鼠的持久反应异种移植物和肺癌的遗传模型。非常出乎意料的是，我们还表明，除了潜在 DNA损伤，两个临床ATR激酶抑制剂（ATRI），具有无关结构，阻止表达免疫检查点蛋白PD-L1并增加了MHC I类抗原在肺癌细胞中的表现 ir。我们的发现，在DNA损伤信号和免疫定位点之间存在串扰尚未存在前面描述，是该提议的重点。免疫抑制途径，称为免疫检查点由肿瘤细胞依次逃避细胞毒性免疫细胞。 PD-1在细胞毒性T上表达细胞及其配体PD-L1在肺癌中进行了更新。 PD-1结合PD-1可防止激活细胞毒性T细胞。免疫检查点使用抗PD-L1和抗PD-1抗体恢复抗肿瘤免疫反应，正在成为一种令人兴奋的肺癌疗法。我们建议ATRI抑制DNA 维修和细胞周期检查点可能会造成顺铂和IR诱导的DNA损伤，同时同时抑制PD-L1表达并恢复抗肿瘤免疫反应。我们在此提案中的目标是定义连接DNA损伤信号传导和免疫检查点的机制。这个目标将是通过以下特定目标完成。目标1：确定ATRI如何抑制肺中的PD-L1表达 IR之后的癌细胞。此目标将定义ATR，ATM，IRF-1，NF-κB和p53对PD-L1的贡献 IR后表达。目标2：确定ATRI如何增加肺癌细胞上的MHC I类表达 IR之后。该目标将确定抑制蛋白质合成和MHC I类的ATR，ATM和P53信号传导 IR之后的演示。目标3：识别ATRI诱导的PDL-1/PD-1免疫切除术中的肺癌封锁 IR之后。 IR后，此目标将确定ATRI诱导的免疫检查点阻断。这这些目标的结果将确定连接DNA损伤信号与免疫自我的机制宽容。这将定义一个新型的热机会来利用ATRI潜在的DNA损伤由顺铂和IR诱导，同时诱导免疫检查点阻滞。

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

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

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

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