Project 1:Therapeutically improving HNSCC antigenicity through epigenetic reprogramming

项目1：通过表观遗传重编程治疗性提高HNSCC抗原性

• 批准号: 10020921
• 负责人: Sara Isabel Pai
• 金额: $ 40.82万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-19 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10020921
• 关键词: Address; Aftercare; Antigen Presentation; Antigens; Bioinformatics; Biological Assay; Biology; Biopsy; Biopsy Specimen; Blood specimen; CD8-Positive T-Lymphocytes; Clinical; Clinical Trials; DNA; DNA Methylation; DNA Methyltransferase Inhibitor; Defect; Down-Regulation; Epigenetic Process; Expression Profiling; Frequencies; Gene Silencing; Generations; Goals; HLA Antigens; Head and Neck Cancer; Head and Neck Squamous Cell Carcinoma; Histocompatibility Antigens Class I; Human Papillomavirus; I-antigen; Immune; Immune Tolerance; Immune system; Immunophenotyping; Immunotherapy; In Vitro; Institution; Location; Malignant Neoplasms; Metastatic/Recurrent; Mutation; Outcome; Patients; Peptides; Pharmaceutical Preparations; Phase; Phase Ib/II Clinical Trial; Population; Reporting; Research Personnel; Science; T-Lymphocyte; Technology; Testing; Therapeutic; Translating; Tumor Antigens; Tumor Immunity; Tumor-Associated Process; antigen processing; cancer cell; cancer genomics; demethylation; epigenetic therapy; immune checkpoint blockade; immune resistance; immunogenic; immunogenicity; improved; in vivo; inhibitor/antagonist; multidisciplinary; neoantigens; neoplastic cell; peripheral blood; programmed cell death ligand 1; programmed cell death protein 1; programs; response; single-cell RNA sequencing; transcriptome sequencing; tumor; tumor immunology

SUMMARY The majority of head and neck squamous cell carcinoma (HNSCC) patients (~80%) do not respond to immune checkpoint blockade (ICB). Increasing evidence highlights two main barriers to achieving clinical response with immunotherapy in HNSCC patients: (i) the tumor's overall poor antigenicity, which limits the generation of antitumor immunity, and (ii) innate and adaptive immune suppressive mechanisms that result in immune tolerance. The overarching goal of this Program Project (P01) is to address these two barriers to improve the low response rates of HNSCC to immunotherapy. Projects 1 and 2 focus on reprogramming tumor cell antigenicity using two different but complementary approaches and Project 3 focuses on converting these antigenic shifts into ones that provoke successful anti-tumor immunity. This Project (Project 1) focuses on reprogramming the antigenicity of the cancers through epigenetic therapy with the goal of enhancing overall tumor antigen presentation and recognition by the immune system. We hypothesize that a DNA methyltransferase inhibitor can uncover epigenetically silenced genes, such as HLA class I APM components and neoantigens across and within heterogeneous tumor cell populations, to uniformly improve tumor cell antigenicity, and, thus, immunogenicity which translates into effective clinical response with immunotherapy. In our proposal, we leverage a collaborative team science approach with multi-disciplinary expertise in HNSCC, cancer immunology, cancer genomics, epigenetics, bioinformatics, HLA biology, and antigen peptide discovery across multiple institutions and an ongoing phase Ib/II investigator-initiated clinical trial administering a DNA methlytransferase inhibitor in combination with ICB in HNSCC patients. Utilizing state of the art technology such as DNA methylation, bulk RNASeq and single-cell RNASeq (scRNASeq) platforms, we plan to comprehensively characterize the pre- and on-treatment biopsy samples to assess changes in expression levels of the HLA class I APM components and identify a panel of shared neoantigen(s) expressed within and across HNSCCs in order to determine whether we are able to successful reprogram the antigenicity of a tumor through epigenetic therapy.

概括 大多数头颈鳞状细胞癌 (HNSCC) 患者 (~80%) 对治疗没有反应 免疫检查点阻断（ICB）。越来越多的证据凸显了实现这一目标的两个主要障碍 HNSCC 患者免疫治疗的临床反应：(i) 肿瘤的整体抗原性较差， 这限制了抗肿瘤免疫的产生，以及（ii）先天性和适应性免疫抑制 导致免疫耐受的机制。该计划项目 (P01) 的总体目标是 解决这两个障碍，以改善 HNSCC 对免疫治疗的低反应率。项目 1和2重点关注使用两种不同但互补的重编程肿瘤细胞抗原性 方法和项目 3 的重点是将这些抗原转变转化为引发 成功的抗肿瘤免疫。该项目（项目 1）侧重于重新编程抗原性 通过表观遗传学治疗癌症，目的是增强整体肿瘤抗原呈递 以及免疫系统的识别。我们假设 DNA 甲基转移酶抑制剂可以 发现表观遗传沉默基因，例如 HLA I 类 APM 成分和新抗原 在异质肿瘤细胞群之间和内部，一致地提高肿瘤细胞抗原性， 因此，免疫原性转化为免疫疗法的有效临床反应。在我们的 建议，我们利用具有多学科专业知识的协作团队科学方法 HNSCC、癌症免疫学、癌症基因组学、表观遗传学、生物信息学、HLA 生物学和抗原 跨多个机构的肽发现和正在进行的 Ib/II 期研究人员发起的临床 一项在 HNSCC 患者中联合使用 DNA 甲基转移酶抑制剂和 ICB 的试验。 利用最先进的技术，例如 DNA 甲基化、批量 RNASeq 和单细胞 RNASeq (scRNASeq) 平台，我们计划全面表征治疗前和治疗中的活检 样本来评估 HLA I 类 APM 成分表达水平的变化并确定 一组在 HNSCC 内和跨 HNSCC 表达的共享新抗原，以确定是否 我们能够通过表观遗传疗法成功地重新编程肿瘤的抗原性。