Department of Medical Oncology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China.
Department of Colorectal Surgery, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, 310003 Zhejiang Province, China.
Cell Rep Med. 2023 Apr 18;4(4):100987. doi: 10.1016/j.xcrm.2023.100987. Epub 2023 Mar 28.
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.
肿瘤微环境（TME）中的免疫代谢及其对结直肠癌（CRC）免疫治疗反应的影响仍不确定。我们在训练和验证队列中对 CRC 患者进行免疫代谢分型（IMS）。确定了 CRC 的三种 IMS 亚型，即 C1、C2 和 C3，它们具有不同的免疫表型和代谢特性。C3 亚型在训练队列和内部验证队列中均表现出最差的预后。单细胞转录组分析揭示了 S100A9 巨噬细胞群体在 C3 中有助于免疫抑制性 TME。通过 PD-1 阻断和 S100A9 抑制剂 tasquinimod 的联合治疗，可以逆转 C3 亚型中功能失调的免疫治疗反应。总之，我们开发了一种 IMS 系统，并鉴定出一种具有最差预后的免疫耐受 C3 亚型。一种基于多组学指导的 PD-1 阻断和 tasquinimod 的联合策略通过在体内耗尽 S100A9 巨噬细胞来提高免疫治疗的反应。
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