Mechanisms of Immunosurveillance for Lung Cancer

描述（由申请人提供）： 在西方世界，肺癌仍然是主要的癌症相关死亡原因，并且针对用于治疗这种疾病的辅助疗法的开发进行了大量的努力。虽然靶向T淋巴细胞形式的适应性免疫应答的免疫疗法已经成功地用于几种实体瘤，如黑素瘤和前列腺癌，但它在肺癌中非常不成功。我们最近发现，与其他实体瘤不同，先天免疫系统而不是适应性免疫系统在肺癌的免疫监视中起着关键作用。此外，自然杀伤细胞（NK细胞）的个体差异在对这种疾病的易感性或抵抗力中发挥作用。本文主要探讨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，我们将研究活化受体NKp46在NK细胞的肺癌特异性活化中的作用。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

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