Vo Duong H T, McGleave Gerard, Overton Ian M
The Patrick G Johnston Centre for Cancer Research, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
Health Data Research Wales and Northern Ireland, Queen's University Belfast, 97 Lisburn Road, Belfast BT9 7AE, UK.
J Pers Med. 2022 Jun 11;12(6):958. doi: 10.3390/jpm12060958.
The therapeutic activation of antitumour immunity by immune checkpoint inhibitors (ICIs) is a significant advance in cancer medicine, not least due to the prospect of long-term remission. However, many patients are unresponsive to ICI therapy and may experience serious side effects; companion biomarkers are urgently needed to help inform ICI prescribing decisions. We present the IMMUNETS networks of gene coregulation in five key immune cell types and their application to interrogate control of nivolumab response in advanced melanoma cohorts. The results evidence a role for each of the IMMUNETS cell types in ICI response and in driving tumour clearance with independent cohorts from TCGA. As expected, 'immune hot' status, including T cell proliferation, correlates with response to first-line ICI therapy. Genes regulated in NK, dendritic, and B cells are the most prominent discriminators of nivolumab response in patients that had previously progressed on another ICI. Multivariate analysis controlling for tumour stage and age highlights CIITA and IKZF3 as candidate prognostic biomarkers. IMMUNETS provide a resource for network biology, enabling context-specific analysis of immune components in orthogonal datasets. Overall, our results illuminate the relationship between the tumour microenvironment and clinical trajectories, with potential implications for precision medicine.
免疫检查点抑制剂（ICI）对抗肿瘤免疫的治疗性激活是癌症医学的一项重大进展，尤其是鉴于有望实现长期缓解。然而，许多患者对ICI治疗无反应，且可能出现严重副作用；迫切需要配套生物标志物来辅助ICI处方决策。我们展示了五种关键免疫细胞类型中的基因共调控免疫网络（IMMUNETS）及其在晚期黑色素瘤队列中用于探究纳武单抗反应控制情况的应用。结果证明了IMMUNETS的每种细胞类型在ICI反应以及利用来自癌症基因组图谱（TCGA）的独立队列推动肿瘤清除方面所起的作用。正如预期的那样，包括T细胞增殖在内的“免疫热”状态与一线ICI治疗反应相关。在先前接受过另一种ICI治疗后病情进展的患者中，在自然杀伤细胞、树突状细胞和B细胞中受调控的基因是纳武单抗反应最显著的判别指标。控制肿瘤分期和年龄的多变量分析突出了Ⅱ类反式激活因子（CIITA）和IKZF3作为候选预后生物标志物。IMMUNETS为网络生物学提供了一种资源，能够对正交数据集中的免疫成分进行特定背景分析。总体而言，我们的结果阐明了肿瘤微环境与临床病程之间的关系，对精准医学具有潜在意义。
