Mechanisms of Immunosurveillance for Lung Cancer

肺癌的免疫监视机制

• 批准号: 8974355
• 负责人: ALEXANDER S. KRUPNICK
• 金额: --
• 依托单位: ST. LOUIS VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-01-01 至 2017-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8974355
• 关键词: Adjuvant Therapy; Adoptive Transfer; Adult; Animal Model; Animals; Applications Grants; Atypical lymphocyte; Cause of Death; Cells; Chromosomes, Human, Pair 19; Chromosomes, Human, Pair 6; Clinical Trials; Defect; Development; Disease; Disease Resistance; Etiology; Genetic Polymorphism; Goals; Growth; Growth and Development function; Health; Histocompatibility Antigens Class I; Human; Immune; Immune System Diseases; Immune system; Immunoglobulins; Immunologic Monitoring; Immunologics; Immunotherapy; In Vitro; Individual; Individual Differences; Inherited; Killer Cells; Licensing; Ligands; Ligation; MHC Class I Genes; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Methods; Mouse Strains; Mus; Mutate; NK Cell Activation; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Play; Population; Predisposition; Process; Prostate; Proteins; Protocols documentation; Recording of previous events; Resistance; Role; Shapes; Smoking; Solid Neoplasm; T-Lymphocyte; Technology; Testing; Tumor Angiogenesis; Tumor Antigens; Vaccination; Variant; Western World; Zinc Fingers; adaptive immunity; arm; base; cancer immunotherapy; cytotoxic; cytotoxicity; endonuclease; fibrosarcoma; immunogenicity; improved; in vivo; kidney cell; man; melanoma; mouse model; pre-clinical; receptor; translational clinical trial; tumor

DESCRIPTION (provided by applicant): Lung cancer remains the major cancer-related cause of death in the Western World and intense efforts are directed toward the development of adjuvant therapy for the treatment of this disease. While immunotherapy targeting the adaptive immune response in the form of T lymphocytes has been successful for several solid tumors, such as melanoma and prostate cancer, it has been extremely unsuccessful in lung cancer. We have recently discovered that, unlike other solid tumors, the innate rather than adaptive immune system plays a critical role in immunosurveillance for lung cancer. Furthermore, individual differences in natural killer cells (NK cells) play a role in susceptibility or resistance to this disease. In this proposal we focus o the role of natural killer cells in immunosurveillance and immunotherapy of lung cancer. We plan to explore mechanistic aspects of lung cancer immunosurveillance in a mouse model and will evaluate the immunologic basis of human susceptibility to this disease. In the first aim we will study the role of the activating receptor NKp46 in lung cancer-specific activation of NK cells. In the second aim we will evaluate the mechanisms used by NK cells to control lung cancer in vivo and in the third aim we will focus on the inhibitory receptor Ly49C as it relates to strain-specifi differences in anti-cancer activity of NK cells. In the fourth and final aim we plan to evaluate th licensing status of human NK cells and susceptibility to lung cancer. 1

描述（由申请人提供）： 肺癌仍然是西方世界与癌症相关的主要死因，人们正在大力努力开发治疗这种疾病的辅助疗法。虽然针对 T 淋巴细胞形式的适应性免疫反应的免疫疗法已成功治疗多种实体瘤，例如黑色素瘤和前列腺癌，但在肺癌方面却极其不成功。我们最近发现，与其他实体瘤不同，先天性而非适应性免疫系统在肺癌的免疫监视中发挥着关键作用。此外，自然杀伤细胞（NK 细胞）的个体差异在对该疾病的易感性或抵抗力中发挥着作用。在本提案中，我们重点关注自然杀伤细胞在肺癌免疫监视和免疫治疗中的作用。我们计划在小鼠模型中探索肺癌免疫监视的机制，并将评估人类对这种疾病易感性的免疫学基础。第一个目标是研究激活受体 NKp46 在肺癌特异性 NK 细胞激活中的作用。在第二个目标中，我们将评估 NK 细胞在体内控制肺癌的机制，在第三个目标中，我们将重点关注抑制性受体 Ly49C，因为它与 NK 细胞抗癌活性的菌株特异性差异有关。在第四个也是最后一个目标中，我们计划评估人类 NK 细胞的许可状态和对肺癌的易感性。 1