Cell reports. Medicine · 2023
An immunometabolism subtyping system identifies S100A9+ macrophage as an immune therapeutic target in colorectal cancer based on multiomics analysis.
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Bao Xuanwen, Wang Danyang, Dai Xiaomeng, Liu Chuan, Zhang Hangyu, Jin Yuzhi, Tong Zhou, Li Bin, Tong Chuchu, Xin Shan, Li Xin, Wang Yanfang, Liu Lulu, Zhu Xudong, Fu Qihan, Zheng Yi, Deng Jingwen, Tian Weihong, Guo Tiannan, Zhao Peng, Chen Wenbin, Fang Weijia
Аннотация
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.