Absence of EGFR signalling in granulocytic cells relieves immunosuppression sensitising CRC metastases to immune checkpoint therapy.

Metastatic colorectal cancer (mCRC) is one of the deadliest cancers with very poor response to immune checkpoint blockade (ICB). Standard therapies employ chemotherapy combined with epidermal growth factor receptor (EGFR) blocking antibodies, which are only effective in a fraction of patients with RAS/RAF wild-type tumours. We have previously shown that EGFR deletion in myeloid cells of CRC, rather than in the cancer cells themselves, reduces tumour growth. Here, we investigate to which extent EGFR blockade in myeloid cells increases anti-tumour immunity, thus sensitising CRC to ICB. Using a syngeneic preclinical CRC liver metastasis model based on the transplantation of murine RAS mutant CRC organoids into mice lacking EGFR in myeloid cells, we observe a reduction in metastasis development accompanied by increased intratumoural T-cell infiltration. Importantly, we demonstrate that EGFR deletion reduces the capacity of granulocytic myeloid-derived suppressor cells (G-MDSCs) to suppress CD4+ T-cell proliferation. RNA-seq analysis of sorted MDSCs and T-cells uncovered an EGFR-dependent signature involved in immunosuppression, which in proficient-mismatch-repair (pMMR) CRC patients is associated with worse overall survival. Therapeutically, lifting immunosuppression by EGFR deletion in myeloid cells sensitised tumours to anti-PD-L1 treatment, thus preventing liver metastasis development. These results imply that anti-EGFR therapies combined with ICB might be successful in preventing metastasis of RAS mutated CRC with high infiltration of suppressive EGFR+ myeloid cells.