HBV 驱动的 CXCR6(+) 耗竭 T 细胞扩增与 CXCL16(+) 巨噬细胞的相互作用：对 HCC 免疫治疗的意义

Hepatitis B virus (HBV) may alter immunotherapy responsiveness in HBV-positive hepatocellular carcinoma (HCC) patients.

However, the underlying immune mechanisms remain unclear. To characterize the immune determinants underlying the enhanced immunotherapy response observed in HBV + HCC patients, we comprehensively analyzed 528 HCC patients who received immunotherapy, encompassing diverse hepatitis infections.

We performed an analysis incorporating single-cell RNA sequencing, spatial transcriptomics, and tissue microarray validation to map the tumor immune landscape. An adoptive T cell transfer combined with anti-programmed death-1 (PD-1) therapy in a syngeneic HCC mouse model was performed to validate key findings.

HBV + HCC patients exhibited superior responses to immunotherapy and prolonged overall survival. Remarkably, HBV + HCC patients harbored an elevated proportion of exhausted CD8 + T cells, and these cells concurrently exhibited enhanced immune activity and cytotoxic potential.

Our study spotlighted a novel subset of exhausted CD8 + T cells, termed PD-1 + CXCR6 + CD8 + T cells. In untreated cases, high levels of PD-1 + CXCR6 + CD8 + T cells correlated with poor prognosis. In contrast, among patients receiving immunotherapy, their enrichment was associated with markedly better outcomes. In vivo , adoptive transfer of CXCR6 + T cells markedly augmented the antitumor efficacy of anti-PD-1 therapy.

Moreover, PD-1 + CXCR6 + CD8 + T cells demonstrated a prominent interaction with CXCL16 + macrophages in HBV + HCC. Taken together, we identified a novel exhausted T cell subset, PD-1 + CXCR6 + CD8 + T cells, that are enriched in HBV + HCC patients and maintained by CXCL16 + macrophages. The enrichment of PD-1 + CXCR6 + CD8 + T cells and their interaction with CXCL16 + macrophages may contribute to the enhanced immunotherapy response observed in HBV + HCC.