Department of Surgical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, Victoria, Australia.
Nat Med. 2021 Aug;27(8):1432-1441. doi: 10.1038/s41591-021-01406-6. Epub 2021 Jul 8.
Treatment with combined immune checkpoint blockade (CICB) targeting CTLA-4 and PD-1 is associated with clinical benefit across tumor types, but also a high rate of immune-related adverse events. Insights into biomarkers and mechanisms of response and toxicity to CICB are needed. To address this, we profiled the blood, tumor and gut microbiome of 77 patients with advanced melanoma treated with CICB, with a high rate of any ≥grade 3 immune-related adverse events (49%) with parallel studies in pre-clinical models. Tumor-associated immune and genomic biomarkers of response to CICB were similar to those identified for ICB monotherapy, and toxicity from CICB was associated with a more diverse peripheral T-cell repertoire. Profiling of gut microbiota demonstrated a significantly higher abundance of Bacteroides intestinalis in patients with toxicity, with upregulation of mucosal IL-1β in patient samples of colitis and in pre-clinical models. Together, these data offer potential new therapeutic angles for targeting toxicity to CICB.
联合免疫检查点阻断（CICB）针对 CTLA-4 和 PD-1 的治疗与多种肿瘤类型的临床获益相关，但也伴随着较高的免疫相关不良事件发生率。因此，需要深入了解 CICB 的反应和毒性的生物标志物和机制。为了解决这一问题，我们对 77 例接受 CICB 治疗的晚期黑色素瘤患者的血液、肿瘤和肠道微生物组进行了分析，其中任何≥3 级的免疫相关不良事件发生率较高（49%），同时在临床前模型中进行了平行研究。CICB 反应的肿瘤相关免疫和基因组生物标志物与 ICB 单药治疗中确定的生物标志物相似，而 CICB 的毒性与更多样化的外周 T 细胞库有关。肠道微生物组的分析表明，毒性患者的肠道拟杆菌（Bacteroides intestinalis）丰度显著增加，患者结肠炎样本和临床前模型中黏膜 IL-1β 上调。这些数据共同为 CICB 的毒性靶向治疗提供了潜在的新治疗角度。
