CCR5andCCL5gene expression in colorectal cancer: comprehensive profiling and clinical value

Abstract

BackgroundThe C-C motif chemokine receptor 5 (CCR5)/C-C motif chemokine ligand 5 (CCL5) axis plays a major role in colorectal cancer (CRC). We aimed to characterize the molecular features associated withCCR5/CCL5expression in CRC and to determine whetherCCR5/CCL5levels could impact treatment outcomes.Methods7604 CRCs tested with NextGen Sequencing on DNA and RNA were analyzed. Molecular features were evaluated according toCCR5andCCL5tumor gene expression quartiles. The impact on treatment outcomes was assessed in two cohorts, including 6341 real-world patients and 429 patients from the Cancer and Leukemia Group B (CALGB)/SWOG 80405 trial.ResultsCCR5/CCL5expression was higher in right-sided versus left-sided tumors, and positively associated with consensus molecular subtypes 1 and 4. HigherCCR5/CCL5expression was associated with higher tumor mutational burden, deficiency in mismatch repair and programmed cell death ligand 1 (PD-L1) levels. Additionally, highCCR5/CCL5were associated with higher immune cell infiltration in the tumor microenvironment (TME) of MMR proficient tumors. Ingenuity pathway analysis revealed upregulation of the programmed cell death protein 1 (PD-1)/PD-L1 cancer immunotherapy pathway, phosphatase and tensin homolog (PTEN) and peroxisome proliferator-activated receptors (PPAR) signaling, and cytotoxic T-lymphocyte antigen 4 (CTLA-4) signaling in cytotoxic T lymphocytes, whereas several inflammation-related pathways were downregulated. LowCCR5/CCL5expression was associated with increased benefit from cetuximab-FOLFOX treatment in the CALGB/SWOG 80405 trial, where significant treatment interaction was observed with biologic agents and chemotherapy backbone.ConclusionsOur data show a strong association betweenCCR5/CCL5gene expression and distinct molecular features, gene expression profiles, TME cell infiltration, and treatment benefit in CRC. Targeting the CCR5/CCL5 axis may have clinical applications in selected CRC subgroups and may play a key role in developing and deploying strategies to modulate the immune TME for CRC treatment.