Project 1:Therapeutically improving HNSCC antigenicity through epigenetic reprogramming

摘要 大多数头颈部鳞状细胞癌(HNSCC)患者(~80%)对 免疫检查点阻断(ICB)。越来越多的证据突显了实现以下目标的两个主要障碍 HNSCC患者免疫治疗的临床反应：(I)肿瘤的抗原性总体较差， 这限制了抗肿瘤免疫的产生，以及(Ii)先天和获得性免疫抑制 导致免疫耐受的机制。本计划项目的总体目标(P01)是 解决这两个障碍，以提高HNSCC对免疫治疗的低应答率。项目 1和2重点是使用两个不同但互补的基因重新编程肿瘤细胞的抗原性 方法和项目3的重点是将这些抗原转移转化为激发 抗肿瘤免疫成功。本项目(项目1)的重点是重新编程病毒的抗原性 通过表观遗传疗法治疗癌症，目的是提高肿瘤抗原的整体呈递能力 以及免疫系统的识别能力。我们假设一种DNA甲基转移酶抑制剂可以 发现表观遗传沉默的基因，如HLAI类APM成分和新抗原 跨异质肿瘤细胞群体和在异质肿瘤细胞群体内，以统一提高肿瘤细胞抗原性， 因此，免疫原性转化为免疫治疗的有效临床反应。在我们的 建议，我们利用协作团队科学方法与多学科的专业知识在 HNSCC，癌症免疫学，癌症基因组学，表观遗传学，生物信息学，人类白细胞抗原生物学 多个机构的多肽发现和正在进行的Ib/II期研究人员发起的临床 HNSCC患者联合应用DNA甲基转移酶抑制剂和ICB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，我们计划全面描述治疗前和治疗中的活组织检查 以评估人类白细胞抗原I类APM组分表达水平的变化，并确定 共同的新抗原小组(S)在HNSCs内部和之间表达，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。

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.