EGFR deletion in myeloid cells reprograms the immunosuppressive landscape of colorectal cancer

Rákkutatás · Colorectal cancer · EGFR

EGFR deletion in myeloid cells of tumor‑bearing CRC mice reduces tumour growth and reshapes the tumour microenvironment towards a less immunosuppressive state.

Despite advances in the treatment of metastatic colorectal cancer (mCRC), it remains the second leading cause of cancer‑related mortality, with limited effective therapeutic options. While EGFR inhibition is a standard first‑line therapy for mCRC patients lacking KRAS mutations, resistance frequently develops, limiting its clinical benefit. Murine CRC models have shown that EGFR deletion in myeloid cells reduces tumour burden, and the presence of EGFR‑positive myeloid cells is associated with poor prognosis in mCRC patients. However, the role of these cells in the therapeutic response to anti‑EGFR therapies remains poorly understood. In this study, we integrated mouse models, single‑cell RNA sequencing (scRNAseq), proteomics, and patient‑derived mCRC datasets to investigate how EGFR signalling in myeloid cells shapes the tumour microenvironment (TME). In a preclinical therapeutic trial, we demonstrate that EGFR deletion in myeloid cells of tumor‑bearing CRC mice reduced tumour growth, whereas EGFR loss in intestinal epithelial tumour cells alone had no therapeutic impact. EGFR deletion also decreased the abundance of F4/80^hi macrophages, particularly the Spp1^+ and C1qc^+ subsets, and reduced inflammatory pathways like TGFβ, IFNγ, and JAK/STAT signalling in myeloid cells. These changes altered myeloid‑T cell interactions, resulting in a less immunosuppressive TME characterised by reduced immune checkpoint expression. Furthermore, we identified thrombospondin‑1 (THBS1) as a myeloid‑derived ligand interacting with T cells, and confirmed its regulation by EGFR signalling through proteomic analysis. Analysis of human CRC datasets revealed that high EGFR and THBS1 expression correlates with poor patient outcomes.

Elucidating EGFR signalling in tumour‑associated myeloid cells opens a novel therapeutic avenue for mCRC, potentially overcoming resistance to conventional anti‑EGFR antibodies and improving patient prognosis.

Bizonyítékszint: Számítógépes vagy elméleti. Modellből vagy adatbányászatból származó jel.

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