High Infiltration of CD203c+ Mast Cells Reflects Immunosuppression and Hinders Prognostic Benefit in Stage II-III Colorectal Cancer

Abstract

Background Activated mast cells (AMCs) have been fully researched in inflammation and allergic reactions. However, the protumoral role of AMCs and their biomarker CD203c has not yet been investigated in colorectal cancer (CRC). Methods We retrospectively collected 449 postoperative patients with stage II–III CRC at two different hospitals as the training (n=310) and validation (n=139) cohorts. These findings were further validated in the independent cohort (Integration of GSE39582 and GSE17536, n=489). The AMC density was assessed using CD203c staining or the CIBERSORT method. The main analysis was recurrence-free survival (RFS) and overall survival (OS). Results As an independent factor, high AMC infiltration was associated with worse RFS/OS in the training (hazard ratio [HR]=3.437/3.014, all p <0.001) and validation (HR=3.537/2.382, all p <0.001) cohorts. We developed and validated an AMC-based nomogram for better stratification for postoperative recurrence in these two cohorts. The role of AMC density was further validated in the independent cohort. High AMC infiltration was associated with decreased RFS/OS after adjuvant chemotherapy (all p <0.05). Approximately 74.2% of intramural CD203c + AMCs expressed a high level of PD-L1. Multiple immunosuppressive pathways were enriched in high AMC infiltration tumors, including upregulation of the TNF-α/NF-κB and angiogenesis pathways and downregulation of the IFN-γ and IFN-α responses. AMC infiltration was reversely associated with CD8 + T-cell infiltration (all p <0.05). Conclusion High AMC infiltration is associated with worse survival outcomes in stages II–III CRC. AMC density may serve as a potential biomarker for survival benefit in patients receiving adjuvant chemotherapy. This AMC-based nomogram could provide better recurrence stratification. Immunosuppression in tumors with high AMC infiltration might contribute to promoting tumor progression.

Association between Atopic Dermatitis and Colorectal Cancer: TET2 as a Shared Gene Signature and Prognostic Biomarker

“…Li et al found a significant enrichment of immunosuppressive angiogenesis pathways in CRC with high infiltration of activated mast cells. This infiltration was inversely correlated with CD8+ T-cell infiltration, suggesting that high activated mast cell infiltration in the CRC microenvironment may be associated with an immunosuppressive phenotype [34]. Thus, the downregulation of TET2 expression in CRC may lead to an increased infiltration of immune suppressive cells, contributing to a poor prognosis.…”

CXCL6-CXCR2 axis-mediated PD-L2+ mast cell accumulation shapes the immunosuppressive microenvironment in osteosarcoma

“…Mast cell infiltration in tumours has recently been reported [ 27 , 28 ]; unfortunately, the phenotypic characteristics of mast cells and their functions are still poorly understood. Many immune coinhibitory signals are associated with immunosuppression in cancer.…”

The regulatory role and mechanism of mast cells in tumor microenvironment

“…[ [53][54][55][56][57][58][59][60] Breast Cancer • MCs play pivotal roles, influencing tumor immune regulation, angiogenesis, and metastatic progression.…”

“…However, the precise role of MCs in colorectal cancer remains a subject of controversy. Some studies suggest that MCs may promote tumor development [57,58], while others propose that they might have anti-tumor properties [59]. This controversy stems from the multi-functionality and complexity of MCs, exhibiting differential behavior in various stages and types of colorectal cancer [60].…”