Immunotherapeutic Modalities for K-ras Mutant Lung Cancer: Sex- and Cell Type-Specific Roles of IL-6/STAT3 signaling

K-ras 突变型肺癌的免疫治疗方式：IL-6/STAT3 信号传导的性别和细胞类型特异性作用

• 批准号: 9904138
• 负责人: Seyed Javad Mirhassani Moghaddam
• 金额: $ 36.73万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9904138
• 关键词: Antibodies; Antiinflammatory Effect; Biological Models; CCL2 gene; CXCL1 gene; Cancer Etiology; Cessation of life; Characteristics; Chemopreventive Agent; Clinical; Cues; Cytokine Network Pathway; Data Set; Development; Epithelial; Epithelial Cells; Epithelium; Estrogen Receptors; Estrogens; Female; Gene Expression Profile; Genes; Genetic; Genomic approach; Germ Cells; Goals; Human; Immune checkpoint inhibitor; Immunotherapeutic agent; Immunotherapy; Incidence; Inflammation; Inflammatory; Inflammatory Response; Intercept; Interleukin-6; K-ras mouse model; KRAS2 gene; Knowledge; Lung; Lung Neoplasms; Malignant neoplasm of lung; Mediating; Modality; Molecular; Molecular Profiling; Mus; Myeloid Cells; Neutrophil Infiltration; Outcome; Pathogenesis; Pathway interactions; Patients; Pharmacology; Phenotype; Preclinical Testing; Predisposition; Preventive; Preventive Intervention; Process; Prognostic Marker; Receptor Signaling; Regimen; Regulation; Risk; Role; STAT3 gene; Sex Differences; Shapes; Signal Pathway; Signal Transduction; Smoker; Testing; Therapeutic; Therapeutic Effect; Therapeutic Intervention; Woman; cancer cell; cell type; chemokine; clinical predictors; comparative; cytokine; functional genomics; human female; immune checkpoint blockade; improved; inhibitor/antagonist; insight; lung tumorigenesis; mRNA Expression; macrophage; male; men; mortality; mouse model; mutant; neoplastic cell; neutrophil; novel; novel strategies; predictive marker; prevent; programs; protective factors; protein expression; recruit; responders and non-responders; response; sex; sex disparity; therapy resistant; transcriptome sequencing; tumor; tumor microenvironment

Worldwide, lung cancer, particularly K-ras mutant lung cancer, is still the leading cause of cancer mortality because of a high incidence, and a low cure rate. Unfortunately, pharmacologic attempts directly targeting K- ras have thus far failed, clearly indicating that there is an urgent need for novel approaches to bring clinical benefits to patients with this undruggable molecular profile. We recently made an astonishing sex-specific discovery using a mouse model for K-ras-driven lung cancer (CC-LR). We found that deletion of STAT3 in K- ras mutant lung epithelial cells significantly inhibited lung cancer development in female mice but, surprisingly, caused a dramatic enhancement of lung tumorigenesis in male mice. This sex-dependent tumor disparity was accompanied by significant changes of NF-κB regulated target genes and inflammatory response in the lung tumor microenvironment which was regulated by estrogen receptor (ER) signaling. In humans, the risk and outcome of lung cancer are also vastly distinct between men and women, especially for smokers. However, the reason for this sex disparity is poorly understood and extremely underappreciated. It is known that estrogen could have anti-inflammatory effects. However, the interplay between estrogen/ER signaling, and STAT3/NF- κB mediated cytokine network in shaping the lung microenvironment and promotion of lung cancer is unknown. Our novel finding that the crosstalk between STAT3 and ER signaling is an essential regulator of NF-κB mediated cytokine response in K-ras mutant lung tumors provides us with a direct molecular insight into these sex differences. It will facilitate identification of the signaling pathways that lung cancer cells use to recruit and reprogram myeloid cells, thus providing new pathways to intercept for preventive and therapeutic purposes. Accordingly, our goals for this project are to determine the sex and cell type specific mechanistic roles of specific inflammatory signaling cues and functional preventive and therapeutic significance of targeting these inflammatory pathways in the pathogenesis of K-ras mutant lung cancer. Three specific aims are proposed to achieve these goals: (Aim 1) To dissect the sex-specific interplay between STAT3/NF-κB mediated cytokine network and estrogen receptor signaling in K-ras mutant lung tumorigenesis. (Aim 2) To investigate the chemopreventive and therapeutic effects of targeting the IL-6/STAT3 pathway in K-ras mutant lung cancer. (Aim 3) To analyze sex- and cell type-specific global expression programs downstream of mutant K-ras in lung cancer. We expect our study will elucidate sex- and cell-type specific mechanisms that will be fundamental in delineating targets for tailoring rationally directed sex-oriented personalized preventive and therapeutic strategies to overcome K-ras mutant lung tumors. It could also help us to improve the efficacy of currently available immunotherapy regimens, to develop a panel of unique and sex specific clinical predictive and prognostic biomarkers to identify responders and non-responders, and to explore mechanisms of susceptibility or resistance to therapy in these patients.

在世界范围内，肺癌，特别是 K-ras 突变肺癌，仍然是癌症死亡的主要原因 因为发病率高，治愈率低。不幸的是，直接针对 K- 的药理学尝试 ras 迄今为止尚未成功，这清楚地表明迫切需要新的方法来将临床 具有这种不可成药分子特征的患者受益。我们最近做了一个令人惊讶的性别特异性 使用 K-ras 驱动的肺癌 (CC-LR) 小鼠模型进行发现。我们发现K-中STAT3的缺失 ras 突变肺上皮细胞显着抑制雌性小鼠肺癌的发展，但令人惊讶的是， 导致雄性小鼠肺部肿瘤的发生显着增强。这种性别依赖性的肿瘤差异是 伴随着NF-κB调节靶基因和肺部炎症反应的显着变化 肿瘤微环境受雌激素受体（ER）信号调节。对于人类来说，风险和 男性和女性肺癌的结局也有很大差异，尤其是吸烟者。然而， 人们对这种性别差异的原因知之甚少，也极不被重视。据了解，雌激素 可能具有抗炎作用。然而，雌激素/ER 信号传导与 STAT3/NF- 之间的相互作用 κB 介导的细胞因子网络在塑造肺微环境和促进肺癌方面的作用尚不清楚。 我们的新发现是 STAT3 和 ER 信号传导之间的串扰是 NF-κB 的重要调节因子 K-ras 突变肺肿瘤中介导的细胞因子反应为我们提供了对这些突变的直接分子洞察 性别差异。它将有助于鉴定肺癌细胞用于招募和转移的信号通路。 重新编程骨髓细胞，从而为预防和治疗目的提供新的拦截途径。 因此，我们这个项目的目标是确定性别和细胞类型的特定机制作用 特定的炎症信号传导线索以及针对这些信号传导的功能性预防和治疗意义 K-ras 突变肺癌发病机制中的炎症途径。提出了三个具体目标 实现这些目标：（目标 1）剖析 STAT3/NF-κB 介导的性别特异性相互作用 K-ras 突变型肺肿瘤发生中的细胞因子网络和雌激素受体信号传导。 （目标 2） 研究针对 K-ras 中 IL-6/STAT3 通路的化学预防和治疗效果 突变型肺癌。 （目标 3）分析性别和细胞类型特异性的全局表达程序 肺癌中突变型 K-​​ras 的下游。我们希望我们的研究能够阐明性别和细胞类型特异性 制定合理的性别导向目标的机制至关重要 克服 K-ras 突变肺肿瘤的个性化预防和治疗策略。它也可以帮助我们 为了提高目前可用的免疫治疗方案的功效，开发一组独特的和性别的 特定的临床预测和预后生物标志物，以识别有反应者和无反应者，并 探索这些患者对治疗的敏感性或耐药性机制。