Project 1:Therapeutically improving HNSCC antigenicity through epigenetic reprogramming

总结 大多数头颈部鳞状细胞癌（HNSCC）患者（约80%）对化疗无反应。 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患者中免疫疗法的临床反应：（i）肿瘤的总体抗原性差， 其限制了抗肿瘤免疫的产生，和（ii）先天性和适应性免疫抑制 导致免疫耐受的机制。本计划项目（P01）的总体目标是 解决这两个障碍，以改善HNSCC对免疫治疗的低应答率。项目 1和2的重点是使用两种不同但互补的重编程肿瘤细胞抗原性 项目3的重点是将这些抗原转变转化为引起 成功的抗肿瘤免疫。本项目（项目1）的重点是重编程的抗原性 通过表观遗传疗法治疗癌症，目的是增强整体肿瘤抗原呈递 和免疫系统的识别。我们假设DNA甲基转移酶抑制剂可以 发现表观遗传学沉默的基因，如HLA I类APM成分和新抗原 在异质肿瘤细胞群之间和内部，以均匀地提高肿瘤细胞抗原性， 以及由此产生的免疫原性，其转化为免疫疗法的有效临床应答。在我们 建议，我们利用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 多个机构的肽发现和正在进行的Ib/II期临床试验 在HNSCC患者中进行DNA甲基转移酶抑制剂与ICB联合给药的试验。 利用最先进的技术，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，以评估HLA I类APM组分表达水平的变化，并鉴定 在HNSCC内和跨HNSCC表达的一组共享的新抗原，以确定是否 我们能够通过表观遗传疗法成功地重编程肿瘤的抗原性。

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.