Dissecting and targeting mechanisms of genomic instability-triggered immune evasion in RBM10-deficient non-small cell lung cancer

RBM10 缺陷型非小细胞肺癌基因组不稳定性触发免疫逃逸的剖析和靶向机制

• 批准号: 10658049
• 负责人: Ferdinandos Skoulidis
• 金额: $ 37.06万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-05-02 至 2028-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10658049
• 关键词: AXIN1 protein; Alternative Splicing; Animal Model; Biological Assay; Biological Response Modifiers; C-terminal; CD8-Positive T-Lymphocytes; CSF1 gene; CSF1R gene; Cancer Model; Cancer Patient; Cancer cell line; Cell Line; Cell model; Cells; Cessation of life; Clinical; Clinical Trials; Collection; Combination immunotherapy; DNA Damage; DNA Double Strand Break; DNA Repair; DNA Sequence Alteration; Data; Data Set; Event; Exhibits; Exons; Fostering; Foundations; Genomic Instability; Genomics; Growth; Homeostasis; Human; IRF3 gene; Immune; Immune Evasion; Immune checkpoint inhibitor; Immunobiology; Immunocompetent; Immunotherapy; KRAS2 gene; Link; Lung Adenocarcinoma; Macrophage; Mediating; Mediator; Medicine; Minority; Modeling; Molecular; Monoclonal Antibodies; Mus; Mutation; Myeloid Cells; Myeloid-derived suppressor cells; Nivolumab; Non-Small-Cell Lung Carcinoma; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Phase; Phase III Clinical Trials; Phenotype; Platinum; Pre-Clinical Model; Property; Protein Isoforms; Protein Truncation; Publications; RNA Splicing; Randomized; Research Personnel; Resected; STAT3 gene; Sampling; Shapes; Signal Pathway; Signal Transduction; Somatic Mutation; Specimen; TBK1 gene; Therapeutic; Translations; Tumor Escape; Tumor Immunity; Tumor Promotion; Work; anti-PD-L1; chemotherapy; clinical efficacy; clinically significant; immune checkpoint blockade; immune resistance; immunoregulation; in vivo; ipilimumab; loss of function; mouse model; multidisciplinary; mutant; neoplastic cell; novel; participant enrollment; programmed cell death protein 1; recruit; response; tumor; tumor immunology; tumor microenvironment; tumor-immune system interactions; tumorigenesis; tumorigenic

Project Summary/Abstract Oncogenic mutations in KRAS represent the most prevalent genomic driver event in lung adenocarcinoma (LUAD) (~30%) and account for ~25,000 deaths annually in the U.S. Immunotherapy (IO) with immune checkpoint inhibitors (ICI) is active in KRAS-mutant non-small-cell lung cancer (NSCLC), however only a minority of patients exhibit long-lasting responses. Co-occurring genomic alterations can shape the immunobiology of KRAS-mutant NSCLC and impact its response to ICI. Loss-of-function somatic mutations in RBM10, encoding a regulator of alternative splicing (AS), are prevalent in LUAD (~8%) and are significantly enriched in KRAS- mutant NSCLC (~25%). We found that loss of RBM10 in KRAS-mutant NSCLC tumors and cell lines results in DNA double-strand breaks (DSBs) and STING-dependent but cGAS-independent NF-κB signaling, that establish an immunosuppressive tumor microenvironment (TME) – rich in MDSCs and M2-macrophages – and support tumor immune escape. Critically, RD NSCLC exhibit selective sensitivity to anti-CSF1R, that depends on functional CD8+ T-cells. Preliminary evidence points to accumulation of R-loops and distinct STING isoforms as candidate mechanisms that underpin DDR activation and preferential NF-κB engagement in RD cells. Based on our preliminary findings we hypothesize that: 1. In KRAS-mutant NSCLC, RBM10 loss triggers R-loop accumulation and aberrant DDR signaling that support STING-dependent but cGAS-independent pro- tumorigenic NF-κB signaling; 2. Splicing dysregulation upon RBM10 loss promotes STING isoforms that preferentially engage NF-κB over TBK1 and IRF3; 3. RBM10 loss remodels the NSCLC TME and fosters immune evasion 4. The sensitivity of RD NSCLC to ICI can be enhanced by co-targeting STAT3 with TTI-101. In Aim 1, we will dissect the link between RBM10 loss, DDR activation and STING-mediated NFκB signaling and we will assess the contribution of altered R-loop homeostasis and alternative STING splicing to these phenotypes. In Aim 2, we will comprehensively characterize the composition, signaling pathways and functional properties of the RD TME in preclinical models in order to identify critical mediators of immune evasion and we will validate key findings in NSCLC clinical specimens. Finally, in Aim 3, we will determine the impact of RBM10 inactivation on the clinical efficacy of ICI using clinical outcome data/specimens from patients enrolled in two phase 3 clinical trials of durvalumab with or without tremelimumab versus platinum-doublet chemotherapy for previously untreated metastatic NSCLC as well a phase 3 clinical trial of nivolumab/ipilimumab. In addition, we will evaluate co-targeting STAT3 in combination with anti-PD-(L)1 in order to enhance the efficacy of immune checkpoint blockade in RD-NSCLC. Clinical significance: This work will examine a novel link between splicing dysregulation and immune evasion that is mediated by STING and will further seek to develop precision combination immunotherapy approaches for RD NSCLC. The strength of our assembled multi-disciplinary team of experts will facilitate rapid translation of discoveries into clinical advances for NSCLC patients.

项目摘要/摘要 KRAS中的致癌突变代表了肺腺癌中最普遍的基因组驱动因素事件 （LUAD）（约30％），每年在美国免疫疗法（IO）中占25,000人死亡 检查点抑制剂（ICI）在KRAS突变的非小细胞肺癌（NSCLC）中活跃，但是只有少数 患者表现出持久反应。共发生的基因组改变可以塑造 KRAS突变NSCLC并影响其对ICI的反应。 RBM10中功能丧失的体细胞突变，编码 替代剪接的调节剂（AS）在LUAD中普遍存在（〜8％），并且在Kras-中显着富含 突变NSCLC（〜25％）。我们发现KRAS突变NSCLC肿瘤中RBM10的损失导致细胞系导致 DNA双链断裂（DSB）和sting依赖性但与CGAS无关的NF-κB信号，已建立 免疫抑制性肿瘤微环境（TME） - 富含MDSC和M2摩噬噬细胞 - 并支持 肿瘤免疫逃生。至关重要的是，RD NSCLC暴露了对抗CSF1R的选择性敏感性，这取决于 功能CD8+ T细胞。初步证据表明，R环的积累和不同的刺激同工型作为 基于DDR激活并优选RD细胞中的NF-κB的候选机制。基于 我们的初步发现我们假设：1。在KRAS突变NSCLC中，RBM10损失触发R-loop 积累和异常的DDR信号传导支持sting依赖但与CGA无关的促进 肿瘤NF-κB信号传导； 2。在RBM10损失时剪接失调促进了刺痛的同工型 优先在TBK1和IRF3上互动NF-κB； 3。RBM10损失重塑NSCLC TME并促进免疫 逃避4。通过与TTI-101共同靶向STAT3，可以增强RD NSCLC对ICI的敏感性。在AIM 1中， 我们将剖析RBM10损耗，DDR激活和刺激介导的NFκB信号之间的联系，我们将 评估R-loop稳态改变的贡献和对这些表型的替代刺激性剪接。在 AIM 2，我们将全面表征成分，信号通路和功能特性 临床前模型中的RD TME，以识别免疫进化的关键介体，我们将验证 NSCLC临床标本中的主要发现。最后，在AIM 3中，我们将确定RBM10失活的影响 使用临床结果数据/标本的ICI的临床效率 杜瓦卢马布（Durvalumab 未处理的转移性NSCLC以及Nivolumab/ipilimumab的3阶段临床试验。此外，我们将评估 为了提高免疫检查点的效率 RD-NSCLC中的封锁。临床意义：这项工作将检查剪接失调之间的新联系 和免疫进化，它是通过刺激介导的，并将进一步寻求开发精确组合 RD NSCLC的免疫疗法方法。我们组装的多学科专家团队的实力 将有助于将发现快速转化为NSCLC患者的临床进展。