Mechanisms of Immunosurveillance for Lung Cancer

肺癌的免疫监视机制

• 批准号: 9280818
• 负责人: ALEXANDER S. KRUPNICK
• 金额: --
• 依托单位: SALEM 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/9280818
• 关键词: Adaptive Immune System; 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; Histocompatibility Antigens Class I; Human; Immune; Immune System Diseases; Immune System and Related Disorders; Immune system; Immunoglobulins; Immunologic Monitoring; Immunologics; Immunotherapy; In Vitro; Individual; Individual Differences; Inherited; Innate Immune System; 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 immune response; arm; base; cancer immunotherapy; cytotoxic; cytotoxicity; endonuclease; fibrosarcoma; immunogenicity; improved; in vivo; kidney cell; killer immunoglobulin-like receptor; man; melanoma; mouse model; pre-clinical; public health relevance; 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中与癌症相关的主要死亡原因，强烈的努力旨在开发辅助治疗以治疗这种疾病。尽管以T淋巴细胞的形式靶向适应性免疫反应的免疫疗法对于几种实体瘤（例如黑色素瘤和前列腺癌）已经成功，但它在肺癌中一直非常不成功。我们最近发现，与其他实体瘤不同，先天而不是适应性免疫系统在肺癌的免疫监视中起着至关重要的作用。此外，天然杀伤细胞（NK细胞）的个体差异在对这种疾病的敏感性或抗性中起作用。在此提案中，我们将自然杀伤细胞在免疫监视和肺癌免疫疗法中的作用。我们计划在小鼠模型中探索肺癌免疫监视的机械方面，并将评估人类对这种疾病易感性的免疫学基础。在第一个目标中，我们将研究激活受体NKP46在NK细胞的肺癌特异性激活中的作用。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敏感性。 1