αvβ3-induced epithelial cancer progression via macrophage recruitment

通过巨噬细胞募集αvβ3 诱导上皮癌进展

• 批准号: 10391529
• 负责人: Hiromi Inoue Wettersten
• 金额: $ 12.94万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN DIEGO
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10391529
• 关键词: Advanced Malignant Neoplasm; Animal Model; Antibodies; Carcinoma; Cell Adhesion; Cells; Chemicals; Chronic; Communication; Cytotoxic T-Lymphocytes; Data; Development; Drug resistance; Ectopic Expression; Environment; Epithelial; Epithelial Cells; Equipment; Foundations; Goals; Growth; Human; Immune; Immune checkpoint inhibitor; Immune response; Immune system; Immunocompetent; Immunocompromised Host; Immunosuppression; Immunotherapeutic agent; In Vitro; Inflammation; Inflammation Mediators; Inflammatory; Integrin alphaVbeta3; Integrins; KRAS2 gene; Knock-out; Knockout Mice; Knowledge; Laboratories; Link; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Mature T-Lymphocyte; Mediating; Modeling; Mus; Mutant Strains Mice; Neoplasm Metastasis; Nude Mice; Organ; Pharmaceutical Preparations; Phenotype; Process; Publishing; Pulmonary Inflammation; Reporting; Research Personnel; Risk Factors; Testing; Therapeutic; Training; Tumor-associated macrophages; Veterinarians; Work; adhesion receptor; anti-tumor immune response; cancer cell; carcinogenesis; career; cytokine; epithelial to mesenchymal transition; interest; lung cancer cell; lung carcinogenesis; macrophage; mouse model; neoplastic cell; novel; novel therapeutic intervention; prevent; recruit; success; tumor; tumor microenvironment; tumor progression; tumor-immune system interactions

Project Summary/Abstract It has recently become clear that carcinogenesis and cancer progression involves dysregulation of immune cells within the tumor microenvironment. The particular interest of this proposal are how tumor cells develop tactics to manipulate immune cells to facilitate cancer progression, and how chronic inflammation induced immunosuppression accelerates carcinogenesis. Dr. Wettersten recently published that tumor cell expression of a cell adhesion receptor, integrin αvβ3, is associated with the enrichment of tumor-associated macrophages (TAMs), which are known to promote immune suppression and prevent the influx of cytotoxic T cells. Her new preliminary studies reveal that αvβ3 expression on lung cancer cells is sufficient to recruit TAMs and that inflammatory mediators can induce αvβ3 expression both on normal lung epithelium as well as lung cancer cells. Together, these findings suggest inflammation can induce tumor cell expression of αvβ3, which in turn leads to TAM accumulation, immune suppression, and tumor progression. Furthermore, inflammation induced αvβ3 expression on lung epithelium may contribute to the well-known relationship between inflammation and cancer. The overall goals of this study are to understand how αvβ3+ cancer cells promote a pro- tumor/immunosuppressive microenvironment during cancer progression and how αvβ3 expression on normal lung epithelium induces inflammation-mediated carcinogenesis. Aim 1 will determine if TAM enrichment factors from αvβ3+ cancer cells promote an immunosuppressive microenvironment. The goal of Aim 2 is to target integrin αvβ3+ cancer cells to shift the tumor immune profile from pro-tumor to anti-tumor. Aim 3 will assess if inflammation-induced expression of integrin αvβ3 on lung epithelial cells accelerates carcinogenesis. To achieve these aims, the expression of αvβ3 will be genetically modified in immunocompetent mouse models of lung cancer and inflammation to reveal how αvβ3+ cells exploit the immune system to enable cancer development and progression. Understanding this process will lead to the development of novel therapeutic strategies to strengthen the anti-tumor immune response. Dr. Wettersten’s career goal is to become an independent investigator in an academic setting. She will leverage her dual training as a veterinarian and cancer biologist to generate new therapeutic approaches targeting the communication between the tumor microenvironment and cancer cells. While her project is strongly supported by her recent findings with Dr. Cheresh, exploring the impact of αvβ3+ cancer cells in the tumor microenvironment is distinct from Dr. Cheresh’s existing work, and the novel mouse models established in this study will provide a foundation for her to further investigate the cancer cell-microenvironment interaction. Dr. Cheresh and her other collaborators at UCSD will give her access to world-class facilities, equipment, and animal models, providing her with an ideal environment to accomplish the proposed work and launch her career as an independent investigator.

项目总结/摘要 最近已经清楚的是，癌的发生和癌症的进展涉及免疫功能的失调。 肿瘤微环境中的细胞。这项提议特别令人感兴趣的是肿瘤细胞是如何发展的 操纵免疫细胞以促进癌症进展的策略，以及慢性炎症如何诱导 免疫抑制加速癌发生。Wettersten博士最近发表了肿瘤细胞表达 细胞粘附受体整合素αvβ3与肿瘤相关巨噬细胞的富集有关 （TAM），已知其促进免疫抑制并防止细胞毒性T细胞的流入。她的新 初步研究表明，肺癌细胞上的αvβ3表达足以招募TAM， 炎症介质可诱导正常肺上皮和肺癌细胞表达αvβ3。 总之，这些发现表明炎症可以诱导肿瘤细胞表达αvβ3，这反过来又导致 TAM蓄积、免疫抑制和肿瘤进展。此外，炎症诱导αvβ3 在肺上皮上的表达可能有助于炎症和癌症之间的众所周知的关系。 本研究的总体目标是了解αvβ3+癌细胞如何促进促癌细胞增殖。 肿瘤/免疫抑制微环境在癌症进展过程中的作用以及αvβ3在正常 肺上皮诱导炎症介导的癌发生。目标1将确定TAM富集因子 从αvβ3+癌细胞促进免疫抑制微环境。目标2的目标是 整合素αvβ3+癌细胞，以将肿瘤免疫谱从促肿瘤转变为抗肿瘤。目标3将评估是否 炎症诱导的肺上皮细胞上整合素αvβ3的表达加速了癌变。实现 这些目的，αvβ3的表达将在免疫活性小鼠肺模型中进行遗传修饰， 癌症和炎症，揭示αvβ3+细胞如何利用免疫系统使癌症发展 和进步。了解这一过程将导致新的治疗策略的发展， 增强抗肿瘤免疫反应。 Wettersten博士的职业目标是成为学术环境中的独立调查员。她会利用 她作为兽医和癌症生物学家的双重培训，以产生针对癌症的新治疗方法。 肿瘤微环境和癌细胞之间的沟通。虽然她的项目得到了大力支持 她最近与Cheresh博士的研究结果，探索αvβ3+癌细胞在肿瘤中的影响， 微环境与Cheresh博士现有的工作不同，在这种微环境中建立的新型小鼠模型 研究将为她进一步研究癌细胞与微环境的相互作用提供基础。博士 Cheresh和她在UCSD的其他合作者将为她提供世界一流的设施，设备和动物 模特，为她提供了一个理想的环境，以完成拟议的工作，并开始她的职业生涯， 独立调查员