Bao et al. integrated transcriptome, proteome, and single-cell transcriptome analysis to develop immunometabolism molecular subtyping (IMS), which subdivided patient CRC into three subtypes (C1, C2, and C3) with distinct metabolic and immunogenic properties, and associated clinical responses. The C3 subtype exhibited the worst prognosis, had a high abundance of immunosuppressive macrophages, and was enriched for S100A9+ macrophages/monocytes compared to C1 and C2 subtypes. Tasquinimod (an S100A9 inhibitor) and anti-PD-1 dual treatment reprogrammed the pro-tumor M2-type TAMs into antitumor M1-type TAMs and induced a strong antitumor immune response.
Contributed by Shishir Pant
ABSTRACT: 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.
Author Info: (1) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: xuanwen.bao@zju.edu.cn. (2) D
Author Info: (1) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: xuanwen.bao@zju.edu.cn. (2) Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, China. (3) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (4) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (5) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (6) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (7) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (8) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (9) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (10) Department of Genetics, Yale School of Medicine, Yale University, New Haven, CT 06510, USA. (11) German Cancer Research Center (DKFZ), Heidelberg 69120, Germany. (12) Ludwig-Maximilians-Universitt Mnchen (LMU), 80539 Munich, Germany. (13) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (14) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (15) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (16) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (17) Department of Pathology and International Institutes of Medicine, The Women's Hospital, Zhejiang University School of Medicine, Hangzhou 310058, China. (18) Department of Immunology, School of Medicine, Jiangsu University, Zhenjiang, Jiangsu, China. (19) Westlake Laboratory of Life Sciences and Biomedicine, Key Laboratory of Structural Biology of Zhejiang Province, School of Life Sciences, Westlake University, 18 Shilongshan Road, Hangzhou, 310024 Zhejiang Province, China; Institute of Basic Medical Sciences, Westlake Institute for Advanced Study, 18 Shilongshan Road, Hangzhou, 310024 Zhejiang Province, China. (20) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. (21) Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, China. Electronic address: wenbincheng@zju.edu.cn. (22) Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China. Electronic address: weijiafang@zju.edu.cn.
