Project 3: Targeting Vulnerabilities in the Fibrotic Extracellular Matrix (ECM) of Lung Cancers

项目3项目概要/摘要 在基于非小细胞肺癌（NSCLC）的治疗中已经取得了实质性的治疗进展。 对PD-1/PD-L1轴的免疫检查点抑制剂的掺入的影响。不幸的是，大多数 由于原发性或获得性耐药，患者无法从这种单药方法中获益 机制等关于肿瘤浸润性免疫细胞和肿瘤浸润性免疫细胞之间的相互作用， 细胞外基质和肿瘤微环境的动态变化可能会驱动免疫抑制剂的产生， 微环境，这转化为一个主要的未满足的治疗需求。我们多学科的成员 团队（Gibbons、Kurie、Cascone、Yamauchi、Dalby、Wistuba和Wang）在 研究肺癌进展过程中微环境中的肿瘤基质动力学和免疫因子 和免疫治疗的反应。研究人员带来了人类肺癌小鼠模型的专业知识， 临床肿瘤学、免疫治疗、肺癌分子病理学、药物开发和 生物信息学/生物统计学。我们已经从分析人类肺癌标本中获得了初步数据， 和NSCLC的临床前基因工程小鼠模型（GEMM）， 抑制免疫细胞的肿瘤内监视。基于这些发现，我们 假设肿瘤微环境中细胞外基质沉积和胶原交联 抑制肿瘤浸润免疫细胞，促进肿瘤侵袭和转移。通过平行研究， 临床前模型和患者样本的评估，我们将解决这一假设，并探讨临床 翻译机会：1。评估胶原交联酶和纤维化细胞外基质的作用， 基质对鼠和人肺肿瘤的免疫细胞谱的影响; 2.确定免疫治疗 检查点抑制剂（ICI，例如抗PD-（L）1和/或抗CTLA-4）改变细胞外基质组成， 鼠和患者肿瘤中的交联;和3.测试阻断纤维化胶原蛋白的药剂的功效 交联或胶原介导的T细胞抑制，有或没有免疫检查点抑制剂，以逆转 在临床前模型中抑制有效的肿瘤内免疫应答。人类终点是 在我们对关键ECM特征的分析中证明了：A.孢子肿瘤样品; B. 150例配对手术 肿瘤/正常样本和来自先前未经治疗的IB-IIIA期NSCLC患者的>500份血液样本 来自MDACC NSCLC免疫基因组学分析（ICON）研究; C. 44对肿瘤/正常样本，来自 在MDACC NEOSTAR新辅助ICI研究中治疗可切除的I-IIIA期NSCLC的患者;和D. 多激酶抑制剂尼达尼布治疗后患者的肿瘤。

Project 3 Project Summary/Abstract Substantial therapeutic advances have been made in the treatment of non-small cell lung cancer (NSCLC) based on the incorporation of immune checkpoint inhibitors of the PD-1/PD-L1 axis. Unfortunately, the majority of patients do not benefit from this single-agent approach, either due to primary or acquired resistance mechanisms. There is a knowledge gap about the interplay between the tumor-infiltrating immune cells and the dynamic changes in the extracellular matrix and tumor microenvironment that may drive an immunosuppressive microenvironment, which translates into a major unmet therapeutic need. The members of our multidisciplinary team (Gibbons, Kurie, Cascone, Yamauchi, Dalby, Wistuba, and Wang) have a track record of productivity in studying tumor matrix dynamics and immune factors in the microenvironment during lung cancer progression and in response to immune therapy. The investigators bring expertise in mouse modeling of human lung cancer, clinical oncology, immunotherapy, molecular pathology of lung cancer, drug development and bioinformatics/biostatistics. We have developed preliminary data from analysis of human lung cancer specimens and preclinical genetically engineered mouse models (GEMMs) of NSCLC that the deposition and crosslinking of the collagen matrix suppresses intratumoral surveillance by immune cells. Based on these findings, we hypothesize that extracellular matrix deposition and collagen crosslinking in the tumor microenvironment suppress tumor-infiltrating immune cells, facilitating tumor invasion and metastasis. Through parallel study of pre-clinical models and assessment of patient samples, we will address this hypothesis and explore clinical translational opportunities by: 1. evaluating the role of collagen crosslinking enzymes and a fibrotic extracellular matrix on the immune cell profile of murine and human lung tumors; 2. determining how treatment with immune checkpoint inhibitors (ICI, e.g. anti-PD-(L)1 and/or anti-CTLA-4) alters extracellular matrix composition and crosslinking in murine and patient tumors; and 3. testing the efficacy of agents that block fibrotic collagen crosslinking or collagen-mediated T cell suppression, with or without immune checkpoint inhibitors to reverse the suppression of a productive intratumoral immune response in preclinical models. The Human Endpoint is demonstrated in our analysis of key ECM features in: A. SPORE tumor samples; B. 150 paired surgical tumor/normal samples and >500 blood samples from previously untreated patients with stage IB-IIIA NSCLC from the MDACC ImmunogenomiC prOfiling of NSCLC (ICON) study; C. 44 paired tumor/normal samples from patients treated on the MDACC NEOSTAR study of neoadjuvant ICI for resectable stage I-IIIA NSCLC; and D. tumors from patients after treatment with the multi-kinase inhibitor nintedanib.