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-的药物尝试 RAS到目前为止都失败了，这清楚地表明迫切需要新的方法来带来临床 对这种无法用药的分子特征的患者有好处。我们最近做了一个令人惊讶的针对性别的 使用K-ras驱动的肺癌(CC-LR)小鼠模型的发现。我们发现K-STAT3基因的缺失 RAS突变的肺上皮细胞显著抑制雌性小鼠肺癌的发展，但令人惊讶的是， 能显著增强雄性小鼠的肺部成瘤性。这种性别相关的肿瘤差异是 伴随着肺组织中NF-κB调控的靶基因和炎症反应的显著变化 受雌激素受体(ER)信号调节的肿瘤微环境。在人类中，风险和 肺癌的结果在男性和女性之间也有很大的差异，特别是对吸烟者来说。然而， 造成这种性别差异的原因，人们对此知之甚少，也极不了解。众所周知，雌激素 可能有抗炎作用。然而，雌激素/ER信号和STAT3/NF-1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发生中的作用尚不清楚。 我们的新发现是STAT3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对这些变化的直接分子认识 性别差异。它将有助于识别肺癌细胞用来招募和 重新编程髓系细胞，从而提供新的途径，用于预防和治疗目的的拦截。 因此，我们这个项目的目标是确定性别和细胞类型特定的机械性角色 特异性炎症信号转导及靶向这些信号通路的功能预防和治疗意义 K-ras突变型肺癌发病机制中的炎症途径。提出了三个具体目标来 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 细胞因子网络和雌激素受体信号在K-ras突变肺肿瘤发生中的作用。(目标2)至 靶向IL-6/STAT3通路对K-ras细胞的化学防治作用 突变的肺癌。(目标3)分析性别和细胞类型特定的全球表达程序 突变K-ras下游在肺癌中的作用。我们预计我们的研究将阐明性别和细胞类型的特异性 机制将是描述合理指导的性导向的目标的基本机制 克服K-ras突变肺肿瘤的个性化预防和治疗策略。它还可以帮助我们 为了提高目前可用的免疫疗法的疗效，开发一组独特的和性别 特定的临床预测和预后生物标志物，用于识别应答者和无应答者，并 探讨这些患者对治疗敏感或耐药的机制。

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.