(8) Genomic determinants of the T-cell regulome in immune checkpoint blockade

研究综述 免疫检查点阻断(ICB)疗法-包括ipilimumab(IPI；针对细胞毒性T细胞开发 淋巴细胞抗原4)、尼伏卢单抗(Nivo；抗程序性死亡1抗体)及其组合 (IPI/NIVO)-已显示出对黑色素瘤患者的持久生存益处。尽管回复率很高，但有50%的人 患者对这些治疗没有反应。此外，患者经常会出现与免疫相关的不良事件 严重的发病率，大大降低了生活质量。识别ICB结果的生物标记物的努力已经 主要集中在肿瘤微环境上，因为抗肿瘤T细胞免疫是 ICB，焦点主要集中在肿瘤的T细胞浸润上。虽然前景看好的是基于肿瘤的替代品 ICB已被提出，但这些标记单独或结合起来都不能完全解释ICB的可变性 结果。因此，仍有必要确定ICB结果的更强大的生物标记物， 也是更有效和毒性更低的治疗的潜在新靶点。我们提议写一部小说 假设ICB的结果受到宿主免疫的强烈影响，最近的报告表明 受潜在遗传因素的影响。研究表明，T细胞亚群的表型变异， 包括CD8+T细胞，被归因于生殖系遗传变异。在最近的一项研究中，我们证明了这一点 遗传成分映射到非编码的调控基因组，影响T细胞的转录调控 分化和功能。基于这些数据，我们假设循环中的CD8+T细胞，一个主要的目标 在NIVO和IPI/NIVO疗法中，受CD8+非编码调控的种系遗传变异控制 基因组(调节组)，并且这种遗传变异调节ICB的疗效和毒性。的目标是 建议的研究是发现CD8+T细胞调节组的遗传特征，预测ICB的疗效和 毒性。使用来自Nivo和IPI/Nivo临床试验的600名黑色素瘤患者的样本，我们将进行 全基因组测序和全转录组分析的综合分析 外周血预处理CD8+T细胞识别预测ICB的非编码转录组特征 功效(目标1)。我们将使用来自WGS的遗传信息来全面评估开放染色质 在相同的600名患者的治疗前CD8+T细胞的状态下识别表观遗传学特征 遗传遗传变异，预测ICB反应和免疫相关毒性(目标2)。我们的初步数据 在非编码调节组中发现了新的基因组印记，可以预测ICB的反应，具有很高的临床应用价值 准确性，从而在很大程度上支持我们的假设和设计。我们的研究将第一次阐明 遗传抗肿瘤宿主免疫对ICB结局的影响。正如我们所建议的，除了迫在眉睫 对ICB治疗益处的个性化预测的适用性，来自 这两个目的都将揭示CD8+T细胞中潜在影响ICB耐药性的新的转录网络。这些 可能最终成为改进ICB治疗黑色素瘤和其他癌症的新靶点。

RESEARCH SUMMARY Immune checkpoint blockade (ICB) therapies—including ipilimumab (IPI; developed against cytotoxic T lymphocyte-antigen 4), nivolumab (NIVO; anti-programmed death 1 antibody) and their combination (IPI/NIVO)—have demonstrated durable survival benefits in melanoma. Despite high response rates, >50% of patients do not respond to these treatments. In addition, patients often develop immune-related adverse events with severe morbidity, substantially reducing quality of life. Efforts to identify biomarkers of ICB outcomes have mainly centered on the tumor microenvironment because anti-tumor T cell immunity is the primary target of ICB, the focus has been predominantly on tumor T-cell infiltration. While promising tumor-based surrogates of ICB have been proposed, none of these markers alone or in combination fully explains variability in ICB outcome. Hence, there is a continuing need to identify more powerful biomarkers of ICB outcomes that would also serve as potential novel targets for more effective and less toxic treatments. We propose a novel hypothesis that ICB outcomes are strongly impacted by host immunity, shown in recent reports to be influenced by underlying inherited factors. It was demonstrated that phenotypic variation in T-cell subsets, including CD8+ T cells, is attributed to germline genetic variation. In a recent study, we showed that this inherited component maps to the non-coding regulatory genome, impacting transcriptional regulation of T-cell differentiation and function. Based on these data, we hypothesize that circulating CD8+ T cells, a primary target of NIVO and IPI/NIVO therapies, are controlled by germline genetic variation in the CD8+ non-coding regulatory genome (regulome), and that this genetic variability modulates ICB efficacy and toxicity. The goal of the proposed study is to discover inherited signatures of the CD8+ T cell regulome that predict ICB efficacy and toxicity. Using samples from 600 melanoma patients from a clinical trial of NIVO and IPI/NIVO, we will perform a comprehensive analysis of whole-genome sequencing (WGS) and a whole-transcriptome analysis on peripheral blood pre-treatment CD8+ T cells to identify non-coding transcriptome signatures that predict ICB efficacy (Aim 1). We will use the genetic information from WGS to comprehensively assess open chromatin states in pre-treatment CD8+ T cells from the same 600 patients to identify epigenetic signatures controlled by inherited genetic variation, predicting ICB response and immune-related toxicity (Aim 2). Our preliminary data have revealed novel genomic imprints in the non-coding regulome that predict ICB response with high clinical accuracy, thus substantially supporting our hypotheses and design. For the first time, our study will elucidate the effect of inherited anti-tumor host immunity on ICB outcomes. As we suggest, besides imminent applicability to personalized prediction of ICB treatment benefits, the integration of genomic information from both aims will reveal novel transcriptional networks in CD8+ T cells that potentially affect ICB resistance. These may eventually serve as novel targets for improved ICB therapies in melanoma and other cancers.