Role of Radiotherapy-Induced TREM1+ Mono-Macrophages in Rectal Cancer

Phenotypic Plasticity of TREM1+ Mono-Macrophages Mediated by Radiotherapy Combined with Immunochemotherapy in Locally Advanced Rectal Cancer: A Comprehensive Multi-Omics Study

Background Introduction

Rectal cancer is the second leading cause of cancer-related deaths worldwide, accounting for one-third of all colorectal cancer cases. While surgical and neoadjuvant chemoradiotherapy (CRT) approaches are widely recognized for treating locally advanced rectal cancer (LARC), their effectiveness remains suboptimal. The pathological complete response (pCR) rate for traditional treatments ranges from only 15%-30%, and 30% of patients develop distant metastases. These clinical challenges have driven researchers to explore more effective therapeutic strategies. Recently, immune checkpoint inhibitors (ICIs) have shown promising results in various malignancies. However, for the majority of microsatellite stable (MSS) or mismatch repair-proficient (pMMR) rectal cancer patients, the efficacy of single-agent ICIs is significantly limited.

Radiotherapy has been shown to activate systemic antitumor immunity by enhancing antigen presentation and promoting CD8+ T cell infiltration. Simultaneously, studies indicate that the mono-macrophage population in the tumor immune microenvironment (TIME) plays a pivotal role in treatment response. However, the heterogeneity and functional roles of these mono-macrophage subsets remain unclear in many cancer types and have yet to be systematically explored in LARC. Therefore, this study leverages multi-omics analyses to investigate how radiotherapy combined with immunochemotherapy (SIC) influences the dynamic changes of mono-macrophage subsets and their roles in antitumor immunity in LARC.

Paper and Author Information

This paper was led by Haihong Wang, Menglan Zhai, Mingjie Li, and others, with primary authors affiliated with the Institute of Radiation Oncology and Cancer Center at Union Hospital, Tongji Medical College, Huazhong University of Science and Technology. The article was published on January 21, 2025, in the journal Cell Reports Medicine. The title is “Phenotypic plasticity and increased infiltration of peripheral blood-derived TREM1+ mono-macrophages following radiotherapy in rectal cancer,” and the DOI is https://doi.org/10.1016/j.xcrm.2024.101887.


Experimental Study Design

This research was conducted within the framework of a multi-center Phase III clinical trial (NCT04928807) using short-course radiotherapy combined with immunochemotherapy (SIC) as a neoadjuvant treatment strategy. Through multi-omics approaches, the study analyzed pre- and post-treatment peripheral blood and tumor tissue samples from LARC patients to uncover the dynamic changes in mono-macrophage subsets and their relationship to therapy response.

1. Samples and Experimental Design

A total of 59 eligible LARC patients were enrolled, with 5 patients receiving long-course radiotherapy and chemotherapy (LC) and 11 patients receiving SIC. Multi-omics analyses were employed, including bulk RNA sequencing (bulk RNA-seq) of peripheral blood mononuclear cells (PBMCs) and single-cell RNA sequencing (scRNA-seq) of tumor-infiltrating immune cells. Advanced tools such as Seurat, Monocle3, and CellChat were utilized to analyze immune cell dynamics and cell-cell communication.

2. Dynamic Changes in Peripheral Blood Monocyte Subsets

Using large-scale transcriptomic analyses of PBMCs, the study compared pre- and post-treatment gene expression profiles and found that SIC significantly upregulated immune activation-related genes, such as those involved in phagosome formation, TREM1 signaling, and the TLR pathway. Moreover, the activation of the TREM1 (triggering receptor expressed on myeloid cells 1) signaling pathway was prominently enhanced in patients who achieved pCR but not in non-pCR patients.

3. Immune Cell Changes in Tumor Tissue

Through scRNA-seq analysis, SIC was found to significantly alter the composition of immune cell subsets in the TIME, including an increase in monocyte and CD8+ T cell populations and a marked reduction in Tregs and immunosuppressive macrophages. Further analysis revealed that TREM1-expressing monocyte subsets (CCR2+TREM1high MO) accumulated within tumors and differentiated into C1QC+ macrophage subsets (C1QC+ TAM), which demonstrated potent antigen-presenting capacities and pro-inflammatory features.

4. Functional Validation and Mechanistic Exploration

Mouse colorectal cancer models and in vitro studies validated the role of TREM1 in monocyte migration and M1 polarization. The findings revealed that monocytes migrated to tumor sites under radiotherapy-induced recruitment signals and further differentiated into specific TAM subsets. Using the TREM1 blocker LP17, the study confirmed that TREM1 signaling blockade significantly reduced monocyte tumor infiltration and CD8+ T cell activity.


Key Findings

  1. SIC significantly enhances antitumor immune responses, mainly through the recruitment and activation of TREM1+ mono-macrophages and associated inflammatory signaling pathways.
  2. TREM1-mediated polarization of mono-macrophages directly impacts CD8+ T cell infiltration and function.
  3. Dynamic changes in TREM1+ monocytes in both peripheral blood and the TIME are closely associated with treatment response, providing a novel potential predictor for pCR.

Conclusions and Implications

This study unveils, for the first time, the critical role and dynamic mechanisms of TREM1+ mono-macrophages in response to radiotherapy combined with immunochemotherapy. It proposes that TREM1+ monocytes serve as effective predictive biomarkers for treatment response in LARC. Furthermore, TREM1 pathway activation and the associated differentiation of mono-macrophages represent key strategies for enhancing the synergistic effects of localized radiotherapy and systemic immunotherapy. This study has significant implications for precision medicine in LARC and provides new perspectives for optimizing immunotherapy strategies in other solid tumors.


Research Highlights

  1. Utilizing innovative multi-omics analyses, this study systematically elucidates the dynamic changes of mono-macrophages during SIC therapy.
  2. Demonstrates the central role of TREM1 in regulating monocyte migration, differentiation, and antigen presentation.
  3. Proposes TREM1+ monocytes as predictive biomarkers for LARC treatment response, offering potential guidance for personalized clinical approaches.