Immunoregulatory role of lung-resident club cell factors in lung cancer

肺驻留俱乐部细胞因子在肺癌中的免疫调节作用

基本信息

批准号：
10587065
负责人：
NASSER Khaled ALTORKI
金额：
$ 67.92万
依托单位：
WEILL MEDICAL COLL OF CORNELL UNIV
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-02-01 至 2028-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10587065
关键词：
Acute Aftercare Attenuated Biological Markers Biopsy Cancer Patient Cell Line Cell secretion Cells Clinical Clinical Trials Combined Modality Therapy Cytotoxic T-Lymphocytes Development Dose Effectiveness Human Immune checkpoint inhibitor Immune system Immunosuppression Immunotherapy Inflammation Mediators Inflammatory Link Lung Malignant neoplasm of lung Mediating Mediator Medical Metastatic/Recurrent Mus Myelogenous Myeloid Cells Myeloid-derived suppressor cells Natural Killer Cells Neoadjuvant Therapy Non-Small-Cell Lung Carcinoma Operative Surgical Procedures Outcome PD-1 blockade PD-1/PD-L1 Patients Phenotype Plasma Plasma Cells Proteomics Radiation therapy Recurrence Resected Resistance Role Sampling Secretory Cell Signal Transduction T-Cell Activation T-Lymphocyte Testing Therapeutic Tissues Tumor Immunity Tumor Promotion Work arm cancer type cell killing checkpoint therapy effector T cell experience genetic signature immune checkpoint blockade immune modulating agents immunoregulation improved inhibitor insight member molecular targeted therapies mortality mouse model neoplastic cell novel pre-clinical preclinical trial predicting response prognostic pulmonary function response response biomarker treatment response tumor tumor microenvironment tumor progression

项目摘要

Abstract Despite advances in surgery, radiotherapy, and molecular targeted therapies, mortality in non-small cell lung cancer (NSCLC) remains high. Immune checkpoint inhibitors (ICI) targeting the PD-1/PD- L1 axis have been approved for the treatment of advanced NSCLC, yet >70% of the patients experience little clinical benefit due to a variety of immunosuppressive barriers in the tumor microenvironment (TME). Myeloid suppressor cells exert potent immunosuppressive activity in the TME that promotes tumor progression, mediates resistance to immunotherapy, and confers poor outcomes in a variety of cancer types. We have shown that low dose stereotactic body radiation therapy (SBRT) in combination with ICI confers durable anti-tumor immunity resulting in marked tumor regression and improved survival in mouse models of NSCLC. Unexpectedly, we uncovered that SBRT-mediated activation of lung resident Scgb1a1+ club cell secretome is necessary for improving the efficacy of ICI. We identified a set of 8 club cells secretory factors which in combination with PD-1 blockade elicited significant tumor control and improved survival. Mechanistically, club cell factors inhibit myeloid suppressor cells, reduce pro-tumor inflammatory mediators to improve the effectiveness of ICI. Consistent with the preclinical findings, NSCLC patients who responded to neoadjuvant SBRT/ICI therapy showed increased plasma CC10, a member of the club cell secretome factor. These findings have led to the hypothesis that club cell factors selectively inhibit immunosuppressive and proinflammatory function of myeloid suppressor cells to increase the efficacy of immune checkpoint blockade. We further hypothesize that club cell factors may serve as biomarkers of response and recurrence to SBRT/ICI therapy in human NSCLC. Using an integrated preclinical and clinical approach, we will test this hypothesis through two specific aims. Aim 1 will determine the exact identity of the core club cell factor/s and elucidate mechanisms by which they attenuate myeloid suppressor cells to generate durable anti-tumor immunity, and Aim 2 will leverage samples from a clinical trial to determine if club cell-based biomarkers are associated with response therapy and metastatic recurrence following ICI/SBRT therapy in human NSCLC. This work will develop a mechanism-based rationale for the development of club cell factors as selective inhibitors of myeloid suppressor cells and for improving the efficacy of ICI in NSCLC.

抽象的尽管手术，放射疗法和分子靶向疗法的进展，但在非小型中死亡率细胞肺癌（NSCLC）仍然很高。针对PD-1/PD-的免疫检查点抑制剂（ICI） L1轴已被批准用于治疗晚期NSCLC，但> 70％由于肿瘤中的各种免疫抑制作用，几乎没有临床益处微环境（TME）。髓样抑制细胞在该体内发挥有效的免疫抑制活性促进肿瘤进展，介导对免疫疗法的抵抗力的TME，并赋予贫困各种癌症类型的结果。我们已经表明低剂量立体定向体辐射与ICI结合使用的治疗（SBRT）赋予耐用的抗肿瘤免疫力，导致明显 NSCLC小鼠模型中的肿瘤回归和改善的存活率。出乎意料的是，我们发现了 SBRT介导的肺居民SCGB1A1+俱乐部细胞分泌的激活对于提高ICI的功效。我们确定了一组8个俱乐部细胞分泌因素结合PD-1阻滞可引起明显的肿瘤控制和改善的存活率。从机械上讲，俱乐部细胞因子抑制髓样抑制细胞，减少促肿瘤的炎症提高ICI有效性的介体。与临床前发现NSCLC一致对新辅助SBRT/ICI疗法反应的患者显示血浆CC10增加，成员俱乐部细胞分泌因子。这些发现导致了俱乐部细胞因素的假设有选择地抑制髓样抑制细胞的免疫抑制和促炎功能增加免疫检查点阻滞的功效。我们进一步假设俱乐部细胞因素可以作为对人NSCLC中SBRT/ICI治疗的反应和复发的生物标志物。使用综合的临床前和临床方法，我们将通过两个具体目标。 AIM 1将确定核心俱乐部细胞因子的确切身份并阐明它们减弱髓样抑制细胞以产生耐用的抗肿瘤的机制免疫力和AIM 2将利用临床试验中的样本来确定是否基于俱乐部细胞生物标志物与ICI/SBRT后的反应疗法和转移性复发有关人类NSCLC的治疗。这项工作将为开发发展基于机制的理由将俱乐部细胞因子作为髓样抑制细胞的选择性抑制剂的选择，并提高功效 NSCLC中的ICI。