Understanding and Overcoming Resistance to Cancer Immunotherapy Due to Defective Antigen Presentation

了解并克服由于抗原存在缺陷而对癌症免疫治疗产生的耐药性

基本信息

批准号：
10559608
负责人：
Susan M Kaech
金额：
$ 64.2万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-02-06 至 2025-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559608
关键词：
Activated Natural Killer Cell Affect Aftercare Antigen Presentation Biopsy Cell physiology Cell surface Cells Clustered Regularly Interspaced Short Palindromic Repeats Data Defect Development Disease Disease Resistance Down-Regulation Drug resistance Epigenetic Process FDA approved Gene Expression Regulation Genes Genetic Processes Goals Heterozygote Human I-antigen Immune Immune checkpoint inhibitor Immune signaling Immune system Immunocompetent Immunologics Immunotherapy Impairment Knock-out Knowledge Ligands Lung Neoplasms Major Histocompatibility Complex Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic Melanoma Methods Molecular Mutation Natural Killer Cells Non-Small-Cell Lung Carcinoma Pathway interactions Patients Play Proteins Research Resistance Role SMARCA4 gene Signal Pathway Signal Transduction Solid Neoplasm Specimen Squamous Cell Lung Carcinoma Survival Rate System T-Lymphocyte Testing Therapeutic Tissues beta-2 Microglobulin cancer immunotherapy chromatin remodeling epigenetic regulation epigenetic silencing evidence base immune cell infiltrate in vivo in vivo Model innovation insight melanoma mouse model multicatalytic endopeptidase complex neoplastic cell new therapeutic target novel strategies patient derived xenograft model programmed cell death protein 1 programs resistance mechanism response therapeutically effective tumor

项目摘要

In recent years, immunotherapies have transformed the treatment landscape for patients with advanced lung cancer and melanoma, leading to durable responses in a subset of cases but rarely curing patients of the disease. These treatments, in particular, immune checkpoint inhibitors (ICIs) that block inhibitory signals on T- cells, like programmed cell death protein 1 (PD-1), lead to responses in 15-20% of unselected patients with non- small cell lung cancer (NSCLC) and up to 60% of melanoma patients. On the basis of these studies several immune checkpoint inhibitors have been FDA-approved for the treatment of metastatic melanoma and advanced NSCLC. Increasing numbers of patients are receiving these therapies, however many initially benefit from them and eventually develop drug-resistant disease. To date, there is little knowledge of the molecular and cellular mechanisms that underlie acquired resistance to ICIs. As a result, effective therapeutic strategies to treat patients with ICI-resistant disease are lacking. The long-term goal of the research proposed here is to provide mechanistic insight into acquired resistance to ICIs in lung cancer and melanoma and thus contribute to the development of evidence-based approaches to overcome ICI resistance. Our group has pioneered approaches to study mechanisms of acquired resistance to ICIs in lung cancer. Moreover, we have optimized methods for the in vivo analysis of resistance to ICIs in immunocompetent lung cancer and melanoma mouse models. These studies have revealed that impaired MHC I antigen presentation plays a central role in conferring acquired resistance to ICIs. We hypothesize that multiple different mechanisms including genetic alterations, epigenetic changes and altered immune signaling pathways can lead to downregulation of antigen presentation causing resistance to ICIs. Further, we posit that knowledge of these mechanisms and their immunological consequences can be used to devise therapeutic strategies to overcome ICI-resistance. Thus, we propose to leverage our unique experimental systems to: 1) Determine how defects in MHC I antigen presentation in ICI-resistant tumors affect the immune landscape, especially natural killer (NK) cell function, 2) Elucidate the genetic processes that lead to impaired MHC I antigen presentation in ICI-resistant lung cancers and 3) Determine whether epigenetic silencing of genes encoding MHC I APM components can lead to resistance to ICIs. Together, these studies will provide us with a comprehensive understanding of the mechanisms that underlie defects in MHC I antigen presentation in lung tumors and melanomas resistant to immune checkpoint inhibitors and will set the stage for potential new approaches to overcome this resistance.

近年来，免疫疗法改变了晚期肺患者的治疗景观癌症和黑色素瘤，导致一部分病例的持久反应，但很少能治愈患者疾病。这些治疗尤其是免疫检查点抑制剂（ICI），这些抑制剂阻止了抑制剂信号细胞，例如程序性细胞死亡蛋白1（PD-1），导致15-20％的非选择患者的反应小细胞肺癌（NSCLC）和多达60％的黑色素瘤患者。基于这些研究免疫检查点抑制剂已被FDA批准用于治疗转移性黑色素瘤和晚期 NSCLC。越来越多的患者正在接受这些疗法，但是许多人最初从中受益并最终发展出耐药性疾病。迄今为止，对分子和细胞的了解很少基于ICIS抵抗的机制。结果，治疗患者的有效治疗策略缺乏抗ICI疾病。这里提出的研究的长期目标是提供机械深入了解肺癌和黑色素瘤中对ICIS的耐药性，从而有助于发展基于证据的方法来克服ICI抗性。我们的小组采用了研究方法来研究肺癌中对ICI的耐药性的机制。此外，我们采用了对免疫能力肺中ICIS抗性的体内分析的优化方法癌症和黑色素瘤小鼠模型。这些研究表明，MHC I抗原表现受损在赋予对ICI的获得的抵抗力中起着核心作用。我们假设多种不同的机制包括遗传改变，表观遗传变化和免疫信号通路改变可能导致抗原表现的下调导致对ICI的抗性。此外，我们对这些知识有肯定机制和免疫学后果可用于制定克服治疗策略 ICI抗性。这，我们建议利用我们独特的实验系统来：1）确定如何在 ICI耐药性肿瘤中的MHC I抗原表现会影响免疫景观，尤其是天然杀手（NK）细胞功能，2）阐明导致MHC I抗原表现受损的遗传过程肺癌和3）确定编码MHC I APM成分的基因的表观遗传沉默是否可以导致对ICIS的抵抗。这些研究将共同使我们对 MHC I抗原表现出现缺陷的机制，肺肿瘤和黑色素瘤抗性免疫检查点抑制剂，并将为克服这种抗性的潜在新方法奠定基础。