Development of Mouse and Humanized Models to Study Sex Disparities in Tumor Progression and Treatment of NSCLC

开发小鼠和人源化模型来研究肿瘤进展和非小细胞肺癌治疗中的性别差异

• 批准号: 10727735
• 负责人: Joseph William Landry
• 金额: $ 21.77万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10727735
• 关键词: Address; Affect; American Cancer Society; Animals; Apoptotic; Biological; Biological Assay; Breast; Cancer Model; Carboplatin; Castration; Cell Culture Techniques; Cells; Cellular Assay; Chemicals; Clinic; Clinical; Colon; Color; Combination Drug Therapy; Complex; Data; Development; Diagnosis; Diet; Disease; Environment; Estrogens; FDA approved; Female; Flow Cytometry; Future; Genetic; Genetic Predisposition to Disease; Gonadal Steroid Hormones; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunologic Stimulation; Immunotherapy; Incidence; Incubated; Innate Immune System; Kidney; Knowledge; Lewis Lung Carcinoma; Life Style; Literature; Lung Neoplasms; Macrophage; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Monoclonal Antibodies; Mus; Natural Killer Cells; Nature; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Outcome; Ovariectomy; Ovary; Pemetrexed; Pharmaceutical Preparations; Phenotype; Progesterone; Prognosis; Serum; Sex Differences; Smoking; TNFSF10 gene; Testing; Therapeutic; Time; United States; Woman; anti-PD-1; anti-PD-L1; anti-cancer; anti-tumor immune response; cancer diagnosis; cancer therapy; cell killing; chemotherapy; design; gain of function; human disease; improved; improved outcome; in vivo; inhibitor; innovation; lifetime risk; loss of function; lung cancer cell; male; melanoma; men; mortality; mouse development; neoplastic cell; novel; novel therapeutic intervention; patient derived xenograft model; receptor; response; sex; sex disparity; standard of care; therapy outcome; treatment response; tumor; tumor growth; tumor progression; tumor xenograft

Project Summary According to the American Cancer Society, lung cancer is the second most commonly diagnosed cancer in men and women. Outside of the sex-specific cancers, lung cancer and melanoma have the greatest sex disparity, though the exact mechanisms behind these differences are not well understood. In the United States, men have a higher lifetime risk of developing lung cancer and are more likely to develop severe disease than women. Additionally, there are sex disparities in responses to treatment, such as men having better responses to immunotherapies over women. There are multiple factors contributing to this sex disparity including lifestyle choices, sex hormones, and differences in immune response. Our preliminary data shows that two mouse tumors models of lung cancer, CMT-167 and Lewis Lung Carcinoma (LLC), two models of non-small cell lung cancer (NSCLC), grow slower in female than in male mice. This sex difference is dependent on the ovary as tumors in ovariectomized female mice grow equivalent to those in male mice. Innate immune cells (macrophages and NK cells) and more specifically NKG2D receptor activity are required for reduced tumor growth in females. Multi- parameter flow cytometry analysis shows significant sex differences in NSCLC tumor resident innate immune cells. We show that these sex-disparities extend to several chemotherapy and anti-PDL1 immunotherapy treatments. In preliminary in vivo data we show that the sex-disparity in NSCLC tumor growth and the response to chemotherapy requires NK cells. Ex vivo NK cell killing assays show that preincubation of NSCLC cells with female serum, but not male serum or serum from ovariectomized females, stimulates enhanced NK cell activity utilizing the secreted pro-apoptotic factor TRAIL. This ex vivo NK cell assay provides a means to identify bioactive molecules. Based upon this preliminary data, we propose two Aims for our future studies. Aim 1 we will fractionate serum from female mice to identify a biological molecule from female serum required for LLC and CMT-167 sensitization to NK cell killing via TRAIL. The sensitization of LLC and CMT-167 tumor cells in female mice to the effects of TRAIL are proposed to contribute to the observed sex–differences in tumor growth and sensitivity to therapies (both chemotherapy and immunotherapy). For Aim 2, we will determine if the response to standard of care chemotherapies or anti-PD1 immunotherapy using orthotopic CMT-167 and LLC tumor models is dependent on sex. If a sex difference in response is observed, we will characterize the immune responses of male and female mice to lung tumors in the context of these drugs. In summary, this project aims to gain an understanding of the biological mechanisms behind the sex disparities in NSCLC progression and response to treatment, with the hopes of gaining knowledge to inform clinic decisions and treatment of the human disease.

项目摘要 根据美国癌症协会的数据，肺癌是男性第二常见的癌症 和女人。在性别特异性癌症之外，肺癌和黑色素瘤具有最大的性别差异， 尽管这些差异背后的确切机制尚不清楚。在美国，男人有 终身患肺癌的风险更高，并且比女性更可能患上严重疾病。 此外，对治疗的反应中还有性别分布，例如男人对 女性的免疫疗法。有多种因素导致这种性别差异，包括生活方式 选择，性恐怖和免疫反应的差异。我们的初步数据表明两个小鼠肿瘤 肺癌，CMT-167和刘易斯肺癌（LLC）的模型，两种非小细胞肺癌的模型 （NSCLC），女性的生长比男性小鼠慢。这种性别差异取决于卵巢作为肿瘤 卵巢切除的雌性小鼠长于雄性小鼠。先天免疫细胞（巨噬细胞和NK 细胞）和更具体地说的NKG2D受体活性是女性肿瘤生长所必需的。多- 参数流式细胞仪分析显示NSCLC肿瘤居民先天免疫的显着性别差异 细胞。我们表明，这些性别分散性扩展到多种化疗和抗PDL1免疫疗法 治疗。在初步的体内数据中，我们表明NSCLC肿瘤生长的性别差异和反应 进行化学疗法需要NK细胞。离体NK细胞杀死测定法表明，NSCLC细胞与 雌性血清，但不是雌性血清或卵巢雌性的血清，刺激了增强的NK细胞活性 使用分泌的促凋亡因子步道。该离体NK细胞测定法提供了一种识别生物活性的方法 分子。基于这些初步数据，我们提出了两个目标的目标。目标1我们将 来自雌性小鼠的分级血清，以鉴定来自LLC和LLC所需的雌性血清的生物分子 CMT-167对NK细胞通过小径杀死NK细胞的敏感性。 LLC和CMT-167肿瘤细胞的敏感性 提出对小鼠的小鼠的影响，为观察到的性别与肿瘤生长的性别差异和 对疗法的敏感性（化学疗法和免疫疗法）。对于AIM 2，我们将确定是否响应 使用原位CMT-167和LLC肿瘤，用于护理标准化学疗法或抗PD1免疫疗法 模型取决于性。如果观察到性别差异，我们将表征免疫 在这些药物的背景下，雄性和雌性小鼠对肺部肿瘤的反应。总而言之，这个项目的目标 了解NSCLC进展中性别分布背后的生物学机制和 对治疗的反应，希望获得知识，以告知临床决策和对人类的治疗 疾病。