美国德克萨斯大学MD安德森癌症中心Jennifer A. Wargo、法国巴黎萨克雷大学Laurence Zitvogel等研究人员合作发现，肠道微生物群特征与CTLA-4和PD-1联合阻断剂的毒性有关。相关论文于2021年7月8日在线发表在《自然—医学》杂志上。

研究人员表示，针对CTLA-4和PD-1的联合免疫检查点阻断（CICB）治疗与不同肿瘤类型的临床益处相关，但也与免疫相关的不良事件发生率很高。目前需要深入了解生物标志物以及对CICB的反应和毒性机制。

为了解决这个问题，研究人员对77名接受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，并在临床前模型中进行了平行研究。对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，并且来自CICB的毒性与更多样化的外周T细胞库相关。肠道微生物群的分析表明，在具有毒性的患者中肠道拟杆菌的丰度显著更高，在结肠炎患者样本和临床前模型中黏膜IL-1β上调。总之，这些数据为靶向CICB毒性提供了潜在的新治疗角度。 

附：英文原文

Title: Gut microbiota signatures are associated with toxicity to combined CTLA-4 and PD-1 blockade

Author: Miles C. Andrews, Connie P. M. Duong, Vancheswaran Gopalakrishnan, Valerio Iebba, Wei-Shen Chen, Lisa Derosa, Md Abdul Wadud Khan, Alexandria P. Cogdill, Michael G. White, Matthew C. Wong, Gladys Ferrere, Aurlie Fluckiger, Maria P. Roberti, Paule Opolon, Maryam Tidjani Alou, Satoru Yonekura, Whijae Roh, Christine N. Spencer, Irina Fernandez Curbelo, Luis Vence, Alexandre Reuben, Sarah Johnson, Reetakshi Arora, Golnaz Morad, Matthew Lastrapes, Erez N. Baruch, Latasha Little, Curtis Gumbs, Zachary A. Cooper, Peter A. Prieto, Khalida Wani, Alexander J. Lazar, Michael T. Tetzlaff, Courtney W. Hudgens, Margaret K. Callahan, Matthew Adamow, Michael A. Postow, Charlotte E. Ariyan, Pierre-Olivier Gaudreau, Luigi Nezi, Didier Raoult, Catalin Mihalcioiu, Arielle Elkrief, Rossanna C. Pezo, Lauren E. Haydu, Julie M. Simon, Hussein A. Tawbi, Jennifer McQuade, Patrick Hwu, Wen-Jen Hwu, Rodabe N. Amaria, Elizabeth M. Burton, Scott E. Woodman, Stephanie Watowich, Adi Diab, Sapna P. Patel, Isabella C. Glitza, Michael K. Wong, Li Zhao, Jianhua Zhang, Nadim J. Ajami, Joseph Petrosino

Issue&Volume: 2021-07-08

Abstract: 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.

DOI: 10.1038/s41591-021-01406-6

Source: https://www.nature.com/articles/s41591-021-01406-6