黑色素瘤中趋化因子受体共表达的保守图谱定义了 CD8+ T 细胞的功能状态

Cancer immunotherapies, from checkpoint blockade to adoptive cell therapies like tumor-infiltrating lymphocytes (TILs), have revolutionized cancer treatment but are limited by variable efficacy and significant toxicities. A central challenge is identifying ideal T-cell populations that effectively eliminate tumors without causing off-target damage, a distinction not captured by existing biomarkers.

We show that co-expression patterns of chemokine receptors (CRs) CXCR3, CCR5, and CXCR6 on CD8 + T cells provide a functional "code" defining subsets with divergent roles in on-target immunity versus off-target inflammation. In mouse and human melanoma, a triple-positive (CXCR3 + CCR5 + CXCR6 + ) T-cell subset is essential for tumor control, and its genetic signature correlates with positive clinical response, while a distinct CCR5 + CXCR6 + subset drives liver immune-related adverse events (IRAEs).

Crucially, this CR code reveals that immunotherapy actively reshapes T-cell trafficking patterns, uncovering profound heterogeneity within conventional populations and distinguishing potent anti-tumor progenitors from cells predisposed to exhaustion or off-target migration. This work establishes CR co-expression as a practical tool, providing a surface marker-based strategy to identify and enrich optimized T cells for adoptive therapies, thereby offering a framework to uncouple efficacy from toxicity.