Phenotypic plasticity and increased infiltration of peripheral blood-derived TREM1+ mono-macrophages following radiotherapy in rectal cancer

Haihong Wang; Menglan Zhai; Mingjie Li; Chaoqun Han; Lichao Liu; Chuying Huang; Lei Zhao; Dandan Yu; Kaixiong Tao; Jinghua Ren; Zhenyu Lin; Tao Zhang

doi:10.1016/j.xcrm.2024.101887

Phenotypic plasticity and increased infiltration of peripheral blood-derived TREM1⁺ mono-macrophages following radiotherapy in rectal cancer

Cell Rep Med. 2025 Jan 2:101887. doi: 10.1016/j.xcrm.2024.101887. Online ahead of print.

Authors

Haihong Wang¹, Menglan Zhai¹, Mingjie Li¹, Chaoqun Han², Lichao Liu¹, Chuying Huang³, Lei Zhao¹, Dandan Yu¹, Kaixiong Tao⁴, Jinghua Ren¹, Zhenyu Lin⁵, Tao Zhang⁶

Affiliations

¹ 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.
² Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
³ Hubei Selenium and Human Health Institute, The Central Hospital of Enshi Tujia and Miao Autonomous Prefecture, Enshi, China; Hubei Provincial Key Lab of Selenium Resources and Bioapplications, Enshi, China.
⁴ Department of Gastrointestinal Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
⁵ 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. Electronic address: whxhlzy@hust.edu.cn.
⁶ 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. Electronic address: taozhangxh@hust.edu.cn.

PMID: 39793571
DOI: 10.1016/j.xcrm.2024.101887

Abstract

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.

Keywords: TREM1; immunochemotherapy; locally advanced rectal cancer; macrophage phenotypic remodeling; peripheral blood-derived mono-macrophages; short-course radiotherapy.