(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-包括伊匹单抗（IPI;针对细胞毒性T 淋巴细胞抗原4）、纳武单抗（NIVO;抗程序性死亡1抗体）及其组合 (IPI/NIVO）-已证明在黑色素瘤中具有持久的生存益处。尽管答复率很高，但超过50%的 患者对这些治疗没有反应。此外，患者还经常发生免疫相关不良事件 严重的发病率，大大降低了生活质量。识别ICB结果生物标志物的努力 主要集中在肿瘤微环境，因为抗肿瘤T细胞免疫是肿瘤的主要靶点。 ICB的重点主要是肿瘤T细胞浸润。虽然有希望的肿瘤替代物， ICB已经提出，这些标志物中没有一个单独或组合完全解释ICB的变异性 结果。因此，持续需要确定ICB结果的更强大的生物标志物， 也可作为更有效和毒性更低的治疗的潜在新靶点。我们提出了一种新 假设ICB结果受到宿主免疫力的强烈影响，最近的报告显示， 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CD 8 + T细胞在内的免疫缺陷归因于生殖系遗传变异。在最近的一项研究中，我们发现， 遗传成分映射到非编码调控基因组，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CD 8 + T细胞，一个主要的靶点， NIVO和IPI/NIVO疗法的免疫抑制作用，是由CD 8+非编码调节基因中的生殖系遗传变异控制的。 基因组（调节组），这种遗传变异性调节ICB的疗效和毒性。的目标 拟议的研究是发现预测ICB疗效的CD 8 + T细胞调节组的遗传特征， 毒性我们将使用来自NIVO和IPI/NIVO临床试验的600名黑色素瘤患者的样本， 全基因组测序（WGS）的全面分析和全转录组分析， 外周血预处理CD 8 + T细胞以鉴定预测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 来自相同600名患者的治疗前CD 8 + T细胞中的状态，以鉴定由 遗传变异，预测ICB反应和免疫相关毒性（目的2）。我们的初步数据 已经揭示了非编码调节组中的新基因组印记，其预测ICB反应，具有较高的临床应用价值。 准确性，从而大大支持我们的假设和设计。我们的研究将首次阐明 遗传性抗肿瘤宿主免疫对ICB结局的影响。正如我们所建议的，除了即将到来的 ICB治疗益处的个性化预测的适用性，来自 这两个目标都将揭示潜在影响ICB抗性的CD 8 + T细胞中的新型转录网络。这些 可能最终成为改善黑色素瘤和其他癌症ICB疗法的新靶点。

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.