Inflammatory Conditions Promote Resistance to Immune Checkpoint Inhibitors in High Microsatellite Instability Colorectal Cancer

Abstract

Inflammatory conditions are common complications in colorectal cancer (CRC) and play significant roles in tumor progression and immunosuppression. However, the influence of inflammatory conditions on the tumor response to immune checkpoint inhibitors (ICIs) remains unclear. We included a high microsatellite instability (MSI-H) CRC patient whose primary tumor progressed and liver metastasis regressed after Pembrolizumab treatment. An organoid-T cell coculture model demonstrated an inhibited local immune response instead of systemic immunosuppression. Single-cell RNA sequencing suggested that neutrophils suppress the immune microenvironment, mostly through CTLA-4-associated pathways. A cohort of 73 patients with MSI-H CRC who received ICIs were enrolled, among whom inflammatory conditions were correlated with a poor tumor response. We demonstrated that inflammatory conditions in MSI-H CRCs correlate with resistance to ICIs through neutrophil-associated immunosuppression. Additional CTLA-4 blockade may improve the sensitivity to PD-1 blockade. Clinically, inflammatory conditions could predict a poor response to ICIs in MSI-H CRCs.