一个免疫代谢亚型系统，基于多组学分析，将S100A9+巨噬细胞识别为结直肠癌的免疫治疗靶点。
An immunometabolism subtyping system identifies S100A9+ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis.
发表日期：2023 Mar 24
作者：
Xuanwen Bao, Danyang Wang, Xiaomeng Dai, Chuan Liu, Hangyu Zhang, Yuzhi Jin, Zhou Tong, Bin Li, Chuchu Tong, Shan Xin, Xin Li, Yanfang Wang, Lulu Liu, Xudong Zhu, Qihan Fu, Yi Zheng, Jingwen Deng, Weihong Tian, Tiannan Guo, Peng Zhao, Wenbin Cheng, Weijia Fang
来源：
BIOMEDICINE & PHARMACOTHERAPY
摘要：
免疫代谢在肿瘤微环境（TME）中对免疫治疗反应的影响在结直肠癌（CRC）中仍不确定。我们对训练和验证队列中的CRC患者进行了免疫代谢亚型（IMS）分型，鉴定出三种CRC的IMS亚型，分别为C1、C2和C3，具有不同的免疫表型和代谢特性。C3亚型在训练队列和机构内验证队列中均表现出最差的预后。单细胞转录组显示S100A9+巨噬细胞群体在C3中促进了免疫抑制TME。组合应用PD-1阻断和S100A9抑制剂tasquinimod可以逆转C3亚型的功能失调免疫治疗反应。综上所述，我们开发了IMS系统，鉴定出了一种免疫耐受的C3亚型，表现出最差的预后。通过去除体内S100A9+巨噬细胞，多组学引导的PD-1阻断和tasquinimod组合战略提高了免疫治疗的反应。版权所有©2023年作者。Elsevier Inc.保留所有权利。
Immunometabolism in the tumor microenvironment (TME) and its influence on the immunotherapy response remain uncertain in colorectal cancer (CRC). We perform immunometabolism subtyping (IMS) on CRC patients in the training and validation cohorts. Three IMS subtypes of CRC, namely, C1, C2, and C3, are identified with distinct immune phenotypes and metabolic properties. The C3 subtype exhibits the poorest prognosis in both the training cohort and the in-house validation cohort. The single-cell transcriptome reveals that a S100A9+ macrophage population contributes to the immunosuppressive TME in C3. The dysfunctional immunotherapy response in the C3 subtype can be reversed by combination treatment with PD-1 blockade and an S100A9 inhibitor tasquinimod. Taken together, we develop an IMS system and identify an immune tolerant C3 subtype that exhibits the poorest prognosis. A multiomics-guided combination strategy by PD-1 blockade and tasquinimod improves responses to immunotherapy by depleting S100A9+ macrophages in vivo.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.