Augmenting Anti-Tumor Immunity Using Radiation in the Setting of DNA Repair Defects

在 DNA 修复缺陷的情况下使用辐射增强抗肿瘤免疫力

基本信息

批准号：
10042191
负责人：
Gabriel Oliveira Sawakuchi
金额：
$ 43.13万
依托单位：
UNIVERSITY OF TX MD ANDERSON CAN CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-01 至 2023-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10042191
关键词：
Accounting Address Affect American Antigen Targeting Antigens BRCA1 Mutation BRCA1 gene Binding Biological Breast Cancer Model Cancer cell line Cell Line Cell Nucleus Cells Cellular Structures Cessation of life Chromatin Clinical Cytoplasm Cytosol Cytotoxic T-Lymphocytes DNA DNA Damage DNA Repair DNA Repair Disorder DNA lesion Data Defect Dinucleoside Phosphates Disease Goals High Linear Energy Transfer Radiotherapy IRF3 gene Immune Immune Response Genes Immune response Immune signaling Immune system Immunization Immunotherapy Implant Inflammatory Innate Immune Response Interferon Type I Interferons Lead Lesion Linear Energy Transfer Link Low Linear Energy Transfer Radiotherapy Malignant Neoplasms Mammary Neoplasms Mediating Mediator of activation protein Modeling Mus Mutate Outcome PD-1 inhibitors PDL1 inhibitors Pathway interactions Patient-Focused Outcomes Patients Periodicity Pharmacotherapy Photons Poly Adenosine Diphosphate Ribose Polymerase Progression-Free Survivals Protons Radiation Radiation therapy Research Second Messenger Systems Signal Transduction Stimulator of Interferon Genes Systemic Therapy TANK-binding kinase 1 Testing Time Transactivation Transcriptional Activation Tumor Immunity Tumor-infiltrating immune cells United States Up-Regulation Woman Work adaptive immune response alternative treatment anti-tumor immune response base breast cancer progression cell killing combat cytokine ds-DNA homologous recombination immune checkpoint blockade immunogenicity improved inhibitor/antagonist innovation malignant breast neoplasm mouse model mutant neoplasm immunotherapy neoplastic cell outcome forecast patient response physical property pre-clinical recruit response sensor tool transcription factor treatment strategy tumor

项目摘要

Despite the approval of PARP inhibitors for the treatment of advanced BRCA-mutated breast cancer, progres- sion-free survival times are still quite short at only 7 months. This is a significant problem because once PARP inhibitors fail, few systemic treatment options remain and the disease cannot be cured, leading to the need for alternative treatment strategies. One strategy to enhance the immune response to tumors is radiotherapy (RT), which stimulates innate and adaptive immune responses through the release of antigens and immunostimula- tory mediators. However, relatively little is known about the physical mechanisms of RT that elicit immunostim- ulatory signals and how they can be harnessed in the context of DNA damage and DNA repair defects. We propose to investigate how immunostimulatory signals are modulated in the context of RT-induced DNA dam- age and DNA repair defects, particularly BRCA1 mutation. Our preliminary data indicate that BRCA1 mutation in combination with proton RT, a form of RT that induces relatively more clustered DNA lesions compared to photon RT, potentiates higher levels of micronuclei–a precursor of immunostimulation involving the cycling GMP-AMP synthase (cGAS) and stimulator of interferon (IFN) genes (STING) pathways. We hypothesize that DNA repair deficiency in combination with high-LET RT enhances an immune response through the cGAS- STING pathway. To test this we propose to: 1. Determine whether high-LET RT (protons) vs. low-LET RT (photons) influence the immunogenicity of cells with BRCA1 defects via the cGAS-STING pathway. In this aim, we will determine whether protons enhance cGAS-STING sensing pathway mediated anti-tumor im- mune signaling in BRCA1-mutant and PARP inhibited tumors relative to photons. 2. Determine in a BRCA1- defective murine mammary tumor model whether-high LET RT (protons) vs. low-LET RT (photons) in- fluence immunogenicity, alone and in the setting of PARP and PDL1 inhibitors. We will use syngeneic mouse tumor models with and without functional BRCA1 to evaluate the effect of protons vs. photons alone and with PARP and PD1 inhibitors. We will evaluate the differential activation of the cGAS-STING pathway by assessing micronuclei levels and activation of STING, TBK1, IRF3 and IFN-I and by quantifying inflammatory cytokines and alterations in tumor infiltrating immune cell components after RT. Successful completion of this project will generate innovative preclinical data to directly link the quality of RT and activation of cGAS-STING mediated anti-tumor immune signaling. Our research has the potential to define high LET RT as a way to aug- ment the immune response for patients with aggressive, BRCA1-mutated tumors and possibly for other tumors with DNA repair deficiency. Our proposed work is innovative in that it aims to define the effects of clustered DNA lesions generated by high LET RT on BRCA1 mutated tumors in the context of anti-tumor immune re- sponse, findings which may lead to new opportunities for harnessing unique physical properties of RT as a tool to activate the immune system to combat cancer.

尽管批准了PARP抑制剂用于治疗晚期BRCA突变的乳腺癌，但进展 - 不含sion的生存时间在仅7个月时仍然很短。这是一个重要的问题，因为一旦PARP 抑制剂失败，几乎没有系统治疗方案，无法治愈该疾病，导致需要替代治疗策略。增强对肿瘤免疫响应的一种策略是放疗（RT），这通过释放抗原和免疫抑制剂来刺激先天和适应性免疫反应保守党调解人。然而，关于引起免疫接种的RT的物理机制，相对较少了解在DNA损伤和DNA修复缺陷的背景下，如何利用胰岛信号。我们提出研究如何在RT诱导的DNA大坝的背景下调节免疫刺激信号的建议年龄和DNA修复缺陷，尤其是BRCA1突变。我们的初步数据表明BRCA1突变与质子RT结合在一起，一种与相对簇的DNA病变相比，一种RT形式光子RT，电势较高的微核水平 - 涉及循环的免疫刺激的前体 GMP-AMP合酶（CGA）和干扰素（IFN）基因（STING）途径的刺激剂。我们假设这一点 DNA修复缺乏与高LET RT结合使用可增强通过CGAS-的免疫响应 sting路。为了测试这一点，我们建议：1。确定高LET RT（质子）是否与低LET RT （光子）通过CGAS刺途径影响细胞的免疫原性。这个目的，我们将确定质子是否增强了CGAS插入传感途径介导的抗肿瘤IM- 相对于照片，BRCA1突变剂和PARP中的穆恩信号传导抑制了肿瘤。 2。在BRCA1中确定有缺陷的鼠乳腺肿瘤模型是否使RT（质子）与低率RT（光子）IN- 单独和PARP和PDL1抑制剂的环境。我们将使用syngeneic 带有和不具有功能性BRCA1的小鼠肿瘤模型，以评估质子与照片的效果以及PARP和PD1抑制剂。我们将通过通过评估微核水平和刺激的激活，TBK1，IRF3和IFN-I，并通过量化炎症 RT后的细胞因子和肿瘤浸润的免疫细胞成分的改变。成功完成项目将生成创新的临床前数据，以直接链接RT的质量和CGAS的激活介导的抗肿瘤免疫信号传导。我们的研究有可能定义高级RT作为一种方式针对具有攻击性，BRCA1突变肿瘤的患者的免疫激素，并可能针对其他肿瘤 DNA修复缺乏。我们提出的工作具有创新性，因为它旨在定义集群的影响在抗肿瘤的免疫补给的背景下，高rt在BRCA1上产生的DNA病变赞助商，可能会带来新的机会来利用RT作为工具的独特物理特性激活免疫系统以对抗癌症。