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: 10611927
• 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/10611927
• 关键词: Acceleration; Advanced Malignant Neoplasm; Animal Model; Antibodies; Carcinoma; Cell Adhesion; Cells; Chemicals; Chronic; Communication; Cytotoxic T-Lymphocytes; Data; Development; Drug resistance; Ectopic Expression; Environment; Epithelial Cells; Epithelium; 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; Macrophage; 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; 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.

项目摘要/摘要 最近发现，癌症的发生和发展与免疫调节失调有关。 肿瘤微环境中的细胞。这项提案特别关注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，以及慢性炎症是如何引发的 免疫抑制会加速癌症的发生。Wettersten博士最近发表了肿瘤细胞表达 细胞黏附受体整合素αvβ3与肿瘤相关巨噬细胞的聚集有关 (TAMs)，已知可以促进免疫抑制和防止细胞毒性T细胞的涌入。她的新作品 初步研究表明，肺癌细胞上αvβ3的表达足以募集TAMs，并且 炎症介质可诱导正常肺上皮和肺癌细胞表达α-v-β-3。 综上所述，这些发现表明炎症可以诱导肿瘤细胞表达αvβ3，进而导致 蓄积、免疫抑制与肿瘤进展。此外，炎症诱导的αvβ3 肺上皮细胞的表达可能与炎症和癌症之间众所周知的关系有关。 这项研究的总体目标是了解αvβ3+癌细胞如何促进促进- 肿瘤进展过程中的肿瘤/免疫抑制微环境及α-v-β-3在正常状态下的表达 肺上皮可诱导炎症介导的致癌作用。目标1将确定的富集度因素 来自αvβ3+的癌细胞促进免疫抑制微环境。目标2的目标是瞄准 整合素αvβ3+癌细胞将肿瘤免疫图谱从亲肿瘤转变为抗肿瘤。目标3将评估是否 炎症诱导的肺上皮细胞整合素αvβ3表达加速癌变。要实现 这些目标，αvβ3的表达将在免疫活性的小鼠肺模型中进行基因修饰 癌症与炎症：揭示αvβ3+细胞如何利用免疫系统促进癌症发展 和进步。了解这一过程将导致开发新的治疗策略 增强抗肿瘤免疫反应。 韦特斯滕博士的职业目标是成为一名学术领域的独立调查员。她会利用 作为一名兽医和癌症生物学家，她接受过双重培训，以产生针对 肿瘤微环境与癌细胞之间的通讯。虽然她的项目得到了大力支持 根据她最近与切莱什博士的发现，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，在此建立的新的小鼠模型 这项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。Dr。 切里什和她在加州大学圣地亚哥分校的其他合作者将让她接触到世界级的设施、设备和动物 模特，为她提供了一个理想的环境来完成拟议的工作并开始她的职业生涯 独立调查员。