Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
Department of Immunology, University of Toronto, Toronto, ON, Canada.
Nat Commun. 2021 Aug 26;12(1):5137. doi: 10.1038/s41467-021-25432-7.
Serial circulating tumor DNA (ctDNA) monitoring is emerging as a non-invasive strategy to predict and monitor immune checkpoint blockade (ICB) therapeutic efficacy across cancer types. Yet, limited data exist to show the relationship between ctDNA dynamics and tumor genome and immune microenvironment in patients receiving ICB. Here, we present an in-depth analysis of clinical, whole-exome, transcriptome, and ctDNA profiles of 73 patients with advanced solid tumors, across 30 cancer types, from a phase II basket clinical trial of pembrolizumab (NCT02644369) and report changes in genomic and immune landscapes (primary outcomes). Patients stratified by ctDNA and tumor burden dynamics correspond with survival and clinical benefit. High mutation burden, high expression of immune signatures, and mutations in BRCA2 are associated with pembrolizumab molecular sensitivity, while abundant copy-number alterations and B2M loss-of-heterozygosity corresponded with resistance. Upon treatment, induction of genes expressed by T cell, B cell, and myeloid cell populations are consistent with sensitivity and resistance. We identified the upregulated expression of PLA2G2D, an immune-regulating phospholipase, as a potential biomarker of adaptive resistance to ICB. Together, these findings provide insights into the diversity of immunogenomic mechanisms that underpin pembrolizumab outcomes.
循环肿瘤 DNA（ctDNA）的连续监测正在成为一种非侵入性策略，可用于预测和监测 across cancer types 中免疫检查点阻断（ICB）治疗的疗效。然而，目前的数据有限，无法显示接受 ICB 治疗的患者的 ctDNA 动态与肿瘤基因组和免疫微环境之间的关系。在这里，我们对来自 pembrolizumab（NCT02644369）的 II 期篮式临床试验的 73 名晚期实体瘤患者的临床、全外显子组、转录组和 ctDNA 图谱进行了深入分析，涵盖了 30 种癌症类型，并报告了基因组和免疫景观的变化（主要结果）。根据 ctDNA 和肿瘤负担动态分层的患者与生存和临床获益相关。高突变负担、高免疫特征表达和 BRCA2 突变与 pembrolizumab 的分子敏感性相关，而大量拷贝数改变和 B2M 杂合性丢失与耐药性相关。在治疗过程中，T 细胞、B 细胞和髓样细胞群体表达的基因诱导与敏感性和耐药性一致。我们发现，免疫调节磷脂酶 PLA2G2D 的上调表达可能是对 ICB 适应性耐药的潜在生物标志物。总之，这些发现为 pembrolizumab 结果所依赖的免疫基因组机制的多样性提供了见解。
