Senescent-like neutrophils shape angiogenic immunosuppressive niches in colorectal cancer liver metastasis
Key Points
This research investigates the role of senescent-like neutrophils in colorectal cancer liver metastasis and their impact on the immune environment.
Single-cell RNA sequencing and spatial-enhanced-resolution-omics-sequencing were employed to analyze tumor-associated neutrophils in liver metastasis.
Mechanistic insights on the differentiation of TAN1 from other TAN subsets were explored with a focus on the BHLHE40 gene.
Neutrophil-specific knockout of Bhlhe40 in mice was performed to assess its role in anti-tumor immunity.
TAN1 neutrophils exhibit a glycolysis signature and are associated with poor prognosis in liver metastasis.
Knockout of Bhlhe40 increased anti-tumor immunity and inhibited tumor growth in the experimental model.
TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through CCL3L1-CCR1 signaling.
Abstract
Abstract Neutrophils are major players in innate immune immunity. However, their landscape and functions in colorectal cancer liver metastasis (CRLM) remain poorly understood. Here, using single-cell RNA sequencing and spatial-enhanced-resolution-omics-sequencing (Stereo-seq), we provide a comprehensive transcriptional landscape of tumor-associated neutrophils (TANs) in CRLM. Our analysis reveals that a terminally differentiated pro-tumor neutrophils subset (TAN1), characterized by a glycolysis signature and a senescent phenotype, is significantly enriched in liver metastasis and associated with poor prognosis. Mechanistically, TAN1 arises from other TAN subsets through the upregulation of BHLHE40, driven by glucose deprivation in the metastatic microenvironment. Functionally, TAN1 promotes angiogenesis via VEGFA and recruits immunosuppressive macrophages through potential CCL3L1-CCR1 signaling, thereby fostering an angiogenic immunosuppressive niche. As a result, neutrophil-specific knockout of Bhlhe40 in mice significantly promotes anti-tumor immunity and suppresses tumor growth. In sum, our data uncover the critical role of BHLHE40+ senescent-like neutrophils in shaping the immunosuppressive microenvironment of CRLM.
Abstract 6806: Single cell RNA sequencing of human and murine cancers demonstrates metastases-specific neutrophil phenotypes driven by the IL-1β/CXCR2 signaling axis - Disruption of this pathway abrogates neutrophil immunosuppressive effects and reduces tumor burden2024