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 还有女人。在不同性别的癌症中，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还不是很清楚。在美国，男人有 与女性相比，女性一生中患肺癌的风险更高，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 免疫疗法胜过女性。造成这种性别差异的因素有很多，包括生活方式。 选择、性激素和免疫反应的差异。我们的初步数据显示，两种小鼠肿瘤 非小细胞肺癌模型CMT-167和Lewis肺癌(LLC) (非小细胞肺癌)，雌性小鼠的生长速度慢于雄性小鼠。这种性别差异依赖于卵巢作为肿瘤 去卵巢的雌性小鼠与雄性小鼠长得相当。先天免疫细胞(巨噬细胞和NK 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。多个- 流式细胞术参数分析显示非小细胞肺癌肿瘤居住者先天免疫的性别差异 细胞。我们发现，这些性别差异延伸到几种化疗和抗PDL1免疫疗法。 治疗。在初步的活体数据中，我们显示了NSCLC肿瘤生长和反应中的性别差异 化疗需要NK细胞。体外NK细胞杀伤实验表明，NSCLC细胞与 女性血清，而不是男性血清或去卵巢女性的血清，刺激增强的NK细胞活性 利用分泌的促凋亡因子TRAIL。这种体外NK细胞检测提供了一种鉴定生物活性的方法 分子。基于这一初步数据，我们对未来的研究提出了两个目标。目标1我们将 从雌性小鼠血清中分离出LLC和LLC所需的生物分子 CMT-167对TRAIL杀伤NK细胞的增敏作用。LLC和CMT-167肿瘤细胞对女性的增敏作用 小鼠对TRAIL的影响被认为有助于观察到肿瘤生长和性别差异 对治疗(化疗和免疫治疗)的敏感性。对于目标2，我们将确定响应是否 使用CMT-167和LLC原位肿瘤进行标准护理化疗或抗PD1免疫治疗 模特依赖于性别。如果观察到反应的性别差异，我们将描述免疫的特征 在这些药物的背景下，雄性和雌性小鼠对肺癌的反应。总而言之，这个项目旨在 了解非小细胞肺癌进展和发展过程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，为临床决策和人类的治疗提供信息 疾病。