CCR5+ CD8+ T Cells Are Associated with Poor Response to PD-1 Blockade Therapy

Many patients develop poor clinical response to immune checkpoint inhibitors (ICIs), especially PD-1/PD-L1 blockade. However, transcriptomic features of chemokine receptors associated with poor response remain incompletely characterized. We analyzed publicly available single-cell RNA sequencing datasets from non-small-cell lung cancer (NSCLC) and melanoma cohorts, with additional exploratory analyses in hepatocellular carcinoma (HCC) and colorectal cancer datasets. Chemokine receptor expression on CD8+ T cells from clinical responsive and non-responsive samples to anti-PD-1 therapy was systematically profiled. Differential gene expression, cell-state scoring, pseudotime trajectory inference, and ligand–receptor interaction analysis were performed to characterize associated transcriptional states and predicted cellular interactions. CCR5 transcript expression in tumor-infiltrating CD8+ T cells was associated with lower responsiveness to PD-1/PD-L1 blockade therapy. CCR5+ CD8+ T cells exhibited transcriptional features associated with increased exhaustion, reduced stemness, and advanced differentiation. Pseudotime inference suggested progressively increased CCR5 expression along the inferred differentiation trajectory. Ligand–receptor interaction analysis further identified predicted interactions between CCR5+ CD8+ T cells and tumor-associated myeloid cells, with elevated expression of CCL3 and CCL4 observed in myeloid populations from non-responsive tumors. Together, these findings identify transcriptomic associations between CCR5+ CD8+ T cell states and poor clinical response to PD-1 blockade therapy. These observations support the CCL3/4–CCR5 axis as a candidate pathway for future spatial, functional, and experimental validation.