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 PARP 抑制剂已被批准用于治疗晚期 BRCA 突变乳腺癌，但进展仍然有限。无 sion 的生存时间仍然很短，只有 7 个月，这是一个严重的问题，因为一旦 PARP。抑制剂失效，几乎没有全身治疗选择，并且该疾病无法治愈，导致需要增强肿瘤免疫反应的另一种治疗策略是放射治疗（RT），它通过释放抗原和免疫刺激来刺激先天性和适应性免疫反应然而，对于 RT 引起免疫刺激的物理机制知之甚少。调节信号以及如何在 DNA 损伤和 DNA 修复缺陷的情况下利用它们。提议研究在 RT 诱导的 DNA 损伤的背景下如何调节免疫刺激信号年龄和DNA修复缺陷，特别是BRCA1突变，我们的初步数据表明BRCA1突变。与质子 RT 结合使用，质子 RT 是一种 RT 形式，与其他疗法相比，可诱导相对更多的簇状 DNA 损伤光子 RT，增强更高水平的微核——涉及循环的免疫刺激的前体 GMP-AMP 合酶 (cGAS) 和干扰素 (IFN) 基因刺激剂 (STING) 途径。 DNA 修复缺陷与高 LET RT 相结合可通过 cGAS- 增强免疫反应为了测试这一点，我们建议： 1. 确定高 LET RT（质子）还是低 LET RT （光子）通过 cGAS-STING 通路影响 BRCA1 缺陷细胞的免疫原性。为了实现这一目标，我们将确定质子是否增强 cGAS-STING 传感途径介导的抗肿瘤免疫 BRCA1 突变体和 PARP 中的 mune 信号传导相对于光子抑制肿瘤 2. 在 BRCA1- 中进行测定。有缺陷的小鼠乳腺肿瘤模型无论是高 LET RT（质子）还是低 LET RT（光子）影响免疫原性，单独使用以及在 PARP 和 PDL1 抑制剂的情况下我们将使用同基因。具有和不具有功能性 BRCA1 的小鼠肿瘤模型，用于评估质子与单独光子的效果我们将通过 PARP 和 PD1 抑制剂评估 cGAS-STING 通路的差异激活。评估微核水平和 STING、TBK1、IRF3 和 IFN-I 的激活，并通过量化炎症 RT 成功完成后，细胞因子和肿瘤浸润免疫细胞成分的变化。该项目将生成创新的临床前数据，将 RT 的质量与 cGAS-STING 的激活直接联系起来我们的研究有可能将高 LET RT 定义为一种增强免疫信号的方法。调节患有侵袭性 BRCA1 突变肿瘤以及可能其他肿瘤的患者的免疫反应我们提出的工作是创新的，因为它旨在定义簇的影响。在抗肿瘤免疫治疗背景下，高 LET RT 对 BRCA1 突变肿瘤产生的 DNA 损伤响应，这些发现可能会为利用 RT 的独特物理特性作为工具带来新的机会激活免疫系统来对抗癌症。