Wang Haihong, Zhai Menglan, Li Mingjie, Han Chaoqun, Liu Lichao, Huang Chuying, Zhao Lei, Yu Dandan, Tao Kaixiong, Ren Jinghua, Lin Zhenyu, Zhang Tao
Cancer Center, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Institute of Radiation Oncology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Hubei Key Laboratory of Precision Radiation Oncology, Wuhan, China.
Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
Cell Rep Med. 2025 Jan 21;6(1):101887. doi: 10.1016/j.xcrm.2024.101887. Epub 2025 Jan 9.
In our previously reported phase 2 and phase 3 studies, the combination of short-course radiotherapy and neoadjuvant immunochemotherapy (SIC) is established as effective cancer therapies for locally advanced rectal cancer (LARC). Here, we apply multi-omic analyses to paired pre- and post-treatment LARC specimens undergoing SIC. The peripheral blood-derived TREM1 mono-macrophage subsets that display a pro-inflammatory phenotype are identified and correlate with complete response to SIC. Mechanically, ionizing radiation (IR) induces peripheral TREM1 mono-macrophage expansion in tumors. Following IR, the loss of TREM1 in mono-macrophages undermines antitumor immunity by altering mono-macrophage differentiation and inhibiting CD8 T cell infiltration and activation. The TREM1 mono-macrophage response may rely on activation of key inflammatory pathways, including nuclear factor κB (NF-κB) signaling and Toll-like receptor pathway. Pharmacological inhibition of TREM1 signaling abolishes IR-induced immunoactivation and reduces combined IR and/or anti-PD-1 treatment. Thus, we establish a crucial role of a mono-macrophage state in mediating effective cancer therapy.
在我们之前报道的2期和3期研究中，短程放疗和新辅助免疫化疗（SIC）的联合被确立为局部晚期直肠癌（LARC）的有效癌症治疗方法。在此，我们对接受SIC治疗的LARC配对治疗前和治疗后标本进行多组学分析。我们鉴定出显示促炎表型的外周血来源的TREM1单巨噬细胞亚群，其与对SIC的完全缓解相关。机制上，电离辐射（IR）诱导肿瘤中外周TREM1单巨噬细胞扩增。IR后，单巨噬细胞中TREM1的缺失通过改变单巨噬细胞分化并抑制CD8 T细胞浸润和活化而破坏抗肿瘤免疫。TREM1单巨噬细胞反应可能依赖于关键炎症途径的激活，包括核因子κB（NF-κB）信号传导和Toll样受体途径。TREM1信号传导的药理学抑制消除了IR诱导的免疫激活，并降低了IR和/或抗PD-1联合治疗的效果。因此，我们确立了单巨噬细胞状态在介导有效癌症治疗中的关键作用。
