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

在世界范围内，肺癌，特别是K-ras突变型肺癌，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- ras迄今为止都失败了，这清楚地表明迫切需要新的方法来将临床 对具有这种不可用药的分子特征的患者有益。我们最近做了一个惊人的性别特异性 使用K-ras驱动的肺癌（CC-LR）的小鼠模型的发现。我们发现，在K- ras突变的肺上皮细胞显著抑制雌性小鼠中的肺癌发展，但是，令人惊讶的是， 导致雄性小鼠肺肿瘤发生率显著增加。这种性别依赖的肿瘤差异是 并伴有肺组织NF-κB调控靶基因和炎症反应的明显改变 雌激素受体（ER）信号调节肿瘤微环境。在人类中， 男性和女性肺癌的预后也有很大差异，尤其是对吸烟者而言。但 人们对这种性别差异的原因知之甚少，认识也极为不足。众所周知，雌激素 可能有抗炎作用然而，雌激素/ER信号传导和STAT 3/NF-κ B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中的作用尚不清楚。 我们的新发现是STAT 3和ER信号之间的串扰是NF-κB的重要调节因子 K-ras突变型肺肿瘤中介导的细胞因子反应为我们提供了直接的分子见解， 性别差异它将有助于识别肺癌细胞用于招募和治疗的信号通路。 重编程骨髓细胞，从而提供新的途径，拦截预防和治疗的目的。 因此，我们这个项目的目标是确定性别和细胞类型的具体机制作用， 特异性炎症信号传导线索以及靶向这些信号传导的功能性预防和治疗意义 炎症通路在K-ras突变型肺癌发病机制中的作用提出了三个具体目标， （目的1）研究STAT 3/NF-κB介导的细胞凋亡与性别特异性的相互作用， 细胞因子网络和雌激素受体信号在K-ras突变型肺肿瘤发生中的作用(Aim 2）至 研究靶向K-ras中IL-6/STAT 3通路的化学预防和治疗作用 突变型肺癌(Aim 3）分析性别和细胞类型特异性的全局表达程序 突变型K-ras基因的下游。我们希望我们的研究将阐明性别和细胞类型特异性 机制，将是根本的，在划定目标，以适应合理定向的性别导向 个性化的预防和治疗策略，以克服K-ras突变型肺肿瘤。它也可以帮助我们 为了提高目前可用的免疫治疗方案的疗效，开发一组独特的 特异性临床预测和预后生物标志物，以鉴定应答者和非应答者，以及 探索这些患者对治疗的敏感性或耐药性机制。

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.