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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，免疫疗法已经改变了晚期肺结核患者的治疗前景。癌症和黑色素瘤，导致持久的反应，在一个子集的情况下，但很少治愈患者的这些治疗，特别是阻断T-cell上抑制信号的免疫检查点抑制剂（ICI），细胞，如程序性细胞死亡蛋白1（PD-D1），导致15- 20%的非胰腺炎患者的反应，小细胞肺癌（NSCLC）和高达60%的黑色素瘤患者。免疫检查点抑制剂已被FDA批准用于治疗转移性黑色素瘤，越来越多的患者正在接受这些治疗，但许多患者最初受益于这些治疗。并最终发展为耐药疾病。迄今为止，对这种疾病的分子和细胞机制还知之甚少。因此，治疗患者的有效治疗策略，缺乏ICI耐药疾病。这里提出的研究的长期目标是提供机制深入了解肺癌和黑色素瘤对ICI的获得性耐药性，从而有助于循证方法克服ICI耐药。我们的小组开创了研究肺癌对ICI获得性耐药机制的方法。此外，我们还优化了免疫活性肺对ICI耐药性的体内分析方法，这些研究揭示了受损的MHC I抗原呈递，在赋予对ICI的获得性抗性中起着核心作用。我们假设多种不同的机制包括遗传改变、表观遗传改变和改变的免疫信号传导途径，下调抗原呈递导致对ICI的抗性。此外，我们证实了这些知识，机制及其免疫学后果可用于设计治疗策略，以克服因此，我们建议利用我们独特的实验系统来：1）确定 ICI耐药肿瘤中的MHC I抗原呈递影响免疫景观，特别是自然杀伤（NK） 2）阐明导致ICI耐药细胞中MHC I抗原呈递受损的遗传过程， 3）确定编码MHC I APM组分的基因的表观遗传沉默是否可以这些研究将为我们提供一个全面的了解，肺肿瘤和黑色素瘤中MHCI抗原呈递缺陷的机制，免疫检查点抑制剂，并将为克服这种耐药性的潜在新方法奠定基础。