scRNA-seq for the tumor ecosystem of primary and relapsed hepatocellular carcinoma

Hepatocellular carcinoma (HCC) has high relapse and low 5-year survival rates. Single-cell profiling in relapse HCC is necessary to design effective anticancer therapies, including immunotherapies. We profiled the transcriptomes of approximately 17,000 cells, from 18 primary or early-relapse HCC cases. Early-relapse tumors have reduced regulatory T-cells, increased dendritic cells (DCs), and increased infiltrated CD8+ T-cells, compared with primary tumors, which was validated in two independent cohorts. Remarkably, CD8+ T-cells in relapse tumors overexpressed KLRB1 (CD161) and displayed an innate-like low cytotoxic state, with low clonal expansion, unlike the classical exhausted state observed in primary HCC, and the enrichment of these cells was associated with a worse prognosis. Differential gene expression and interaction analyses revealed specific immune evasion mechanisms in recurrent tumor cells that dampen DC antigen presentation and recruit innate-like CD8+ T-cells. Our comprehensive picture of the HCC ecosystem provided new insights into immune evasion mechanisms associated with tumor relapse.