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

• 批准号: 10337040
• 负责人: Susan M Kaech
• 金额: $ 65.55万
• 依托单位: YALE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-02-06 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10337040
• 关键词: 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; Human; I-antigen; Immune; Immune checkpoint inhibitor; Immune signaling; Immune system; Immunocompetent; Immunologics; Immunotherapy; Impairment; Infiltration; Knock-out; Knowledge; Lead; 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; 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

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癌患者的治疗格局