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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要根据美国癌症协会的数据，肺癌是男性中第二常见的癌症除了性别特异性癌症之外，肺癌和黑色素瘤的性别差异最大，尽管这些差异背后的确切机制尚不清楚，但在美国，男性却发现了这一点。与女性相比，终生患肺癌的风险更高，并且更有可能患上严重疾病。此外，对治疗的反应也存在性别差异，例如男性对治疗的反应更好导致这种性别差异的因素有很多，包括生活方式。我们的初步数据显示，两种小鼠的肿瘤存在选择、性激素和免疫反应的差异。肺癌模型，CMT-167 和 Lewis 肺癌 (LLC)，两种非小细胞肺癌模型 (NSCLC)，雌性小鼠的生长速度比雄性小鼠慢，这种性别差异取决于卵巢，因为肿瘤在雌性小鼠中的生长速度较慢。切除卵巢的雌性小鼠的生长速度与雄性小鼠的先天免疫细胞（巨噬细胞和 NK）相当。细胞），更具体地说，NKG2D 受体活性是减少女性肿瘤生长所必需的。参数流式细胞术分析显示 NSCLC 肿瘤固有免疫存在显着的性别差异我们发现这些性别差异延伸到了几种化疗和抗 PDL1 免疫疗法。在初步体内数据中，我们显示非小细胞肺癌肿瘤生长和反应中的性别差异。化疗需要 NK 细胞体外 NK 细胞杀伤试验表明，NSCLC 细胞预孵育。女性血清（而非男性血清或来自卵巢切除女性的血清）可刺激增强的 NK 细胞活性利用分泌的促凋亡因子 TRAIL 这种离体 NK 细胞测定提供了一种鉴定生物活性的方法。根据这些初步数据，我们提出了我们未来研究的两个目标。分离雌性小鼠的血清，以鉴定 LLC 所需的雌性血清中的生物分子 CMT-167 通过 TRAIL 对 NK 细胞杀伤致敏女性中 LLC 和 CMT-167 肿瘤细胞的致敏作用。小鼠对 TRAIL 的影响被认为有助于观察到的肿瘤生长和性别差异对于目标 2，我们将确定对治疗（化疗和免疫治疗）的敏感性。使用原位 CMT-167 和 LLC 肿瘤进行标准护理化疗或抗 PD1 免疫治疗模型取决于性别。如果观察到反应的性别差异，我们将描述免疫的特征。总之，该项目的目的是研究雄性和雌性小鼠在这些药物的背景下对肺部肿瘤的反应。了解 NSCLC 进展中性别差异背后的生物学机制对治疗的反应，希望获得知识来为人类的临床决策和治疗提供信息疾病。