Mechanisms of Immunosurveillance for Lung Cancer-the Role of CD8+ T Cells in Tumor Tolerance Induction

肺癌免疫监视机制——CD8 T细胞在肿瘤耐受诱导中的作用

• 批准号: 10512744
• 负责人: ALEXANDER S. KRUPNICK
• 金额: --
• 依托单位: BALTIMORE 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 2025-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10512744
• 关键词: Acceleration; Adjuvant; Affect; Animal Model; Award; Belief; Blood; CD8-Positive T-Lymphocytes; CD8B1 gene; Cancer Biology; Cancer Patient; Carcinogens; Cause of Death; Cell Line; Cells; Clinical; Clinical Trials; Consumption; Data; Development; Disease; Down-Regulation; Environment; Failure; Gastrointestinal tract structure; Gene Silencing; General Population; Genetic Transcription; Graft Rejection; Growth; Human; Immune Tolerance; Immune response; Immune system; Immunologic Surveillance; Immunologics; Immunotherapy; Interferons; Laboratories; Lewis lung carcinoma cell; Lung; Lung Transplantation; Lymphocyte; Lymphoid; MAGEA3 gene; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of prostate; Mediating; Mediator; Memory; Military Personnel; Modeling; Mucous Membrane; Mus; Natural Killer Cells; Non-Small-Cell Lung Carcinoma; Organ; Organ Transplantation; Patients; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Play; Population; Protocols documentation; Role; Series; Skin; Solid Neoplasm; T cell differentiation; T-Lymphocyte; TNF gene; Techniques; Testing; Tissues; Transplantation; United States; Vaccination; Veterans; Western World; Work; amino acid metabolism; animal data; base; cancer immunotherapy; clinical application; cytokine; cytotoxic; cytotoxicity; high risk; immunoregulation; immunotherapy trials; improved; melanoma; military veteran; mouse model; novel; novel therapeutic intervention; overexpression; pre-clinical; programmed cell death ligand 1; rational design; response; success; synaptogenesis; tissue resident memory T cell; tumor; tumor growth; tumor microenvironment

Lung cancer remains the major cancer-related cause of death in the Western World and intense efforts are directed toward the development of immunotherapy for the treatment of this disease. While immunotherapy targeting cytotoxic T (CD8+ T) lymphocytes has been successful in several malignancies, such as melanoma and prostate cancer, it has demonstrated only limited success in lung cancer. Based on our laboratory’s work in lung transplantation, where we have demonstrated a tolerogenic role for alloreactive CD8+ T cells, we have now generated preclinical animal data which demonstrates that, unlike the case for other malignancies, the presence of conventional CD8+ T cells can accelerate the growth of both transplantable as well as carcinogen-induced lung cancer in a murine model. In this Merit Award application we propose a series of coordinated but non-overlapping specific aims to delineate the tolerogenic role of CD8+ T cells in lung cancer, identify mechanisms responsible for CD8+ T cell-mediated downregulation of the immune response, as well as define the interaction of CD8+ T cells with natural killer cells. This proposal will extend our understanding of lung cancer-specific immunoregulation and generate novel preclinical data that can be utilized for rational design of lung cancer- specific novel therapeutic approaches for Veterans and the general population.

肺癌仍然是西方世界主要的癌症相关死亡原因， 人们致力于开发用于治疗这种疾病的免疫疗法。 虽然靶向细胞毒性T（CD8+ T）淋巴细胞的免疫疗法在几种疾病中取得了成功， 恶性肿瘤，如黑色素瘤和前列腺癌，它已被证明只有有限的成功 在肺癌中。基于我们实验室在肺移植方面的工作，我们有 证明了同种异体反应性CD8+ T细胞的致耐受作用，我们现在已经产生了临床前 动物数据表明，与其他恶性肿瘤的情况不同， 常规的CD8+ T细胞可以加速可移植的以及 致癌物诱发的肺癌。在这次优秀奖申请中，我们建议 一系列协调但不重叠的特异性目的，以描述CD8+的致耐受性作用 肺癌中的T细胞，确定负责CD8+ T细胞介导的下调机制 免疫应答的作用，以及定义CD8+ T细胞与自然杀伤细胞的相互作用。 这一提议将扩展我们对肺癌特异性免疫调节的理解， 产生新的临床前数据，可用于合理设计肺癌特异性 为退伍军人和普通人群提供新的治疗方法。