Global Medical Genetics | 2021
Single-Cell Profiling Explore the Immunologic Mechanisms of Tumor Relapse in Hepatocellular Carcinoma
Abstract
Despite theworldwide decrease in liver cancer incidence and mortality over the past decade, it is still the fourth leading cause of cancer-related death.1 The burden of liver cancer is still serious, especially in China.2 In 2018, more than half of the liver cancer cases and deaths occurred in China.3 Hepatocellular carcinoma (HCC) is the most common subtype of liver cancer, accounting for 75% of all liver cancer cases.4 Surgical resection is the first choice for early-stage HCC, but more than 70% of HCC patients develop recurrent cancer within 5 years after surgery,5 which is the major cause of death in long-term evaluations. Among them, nearly 70% relapsed cases develop an early recurrence within 2 years of surgery.5 However, the precise molecular mechanisms of rapid recurrence remain unclear. Tumor immune microenvironment (TIME) consists of various immune cells; education of tumor cells has become a hot topic in cancer research due to its association with initiation, progression, and recurrence.6 Therefore, profiling the immune contexture of HCC, which is determined by the composition, density, and functional orientation of tumor-infiltrating immune cells, could provide insights into immune escape mechanisms and helpful to design effective therapeutic strategies for recurrent HCC. Single-cell RNA sequencing (scRNA-seq) is the most powerful tool for tumor immune contexture profiling.7 With broad implications for both basic and clinical cancer research, scRNA-seq has already impacted our conceptual understanding of cancer progression in several cancer types. Although the immune contexture detected by scRNAseq in primary HCC has been reported,8 that in early-relapse HCC is still unknown. In a study recently published in Cell, titled “Single-cell landscape of the ecosystem in early-relapse hepatocellular carcinoma,” Sun et al9 examined 16,498 single-cell transcriptomes from 12 primary and 6 early-relapse HCC tumor tissues by scRNA-seq to define immune contexture at the single-cell resolution level. They found that early-relapse HCC had a distinctive immune contexture that is different from primary HCC. Comparedwith primary HCC, the density of regulatory T-cells (Tregs) was decreased and those of dendritic cells (DCs) and infiltrated CD8þ T-cells were increased in early-relapse HCC. Additionally, CD8þ T-cells in primary HCC displayed a classical exhausted state, but those in early-relapse HCC overexpressed CD161 and resided in an innate-like phenotype with low clonal expansion and cytotoxic state. These alterations were associated with a worse prognosis in HCC. The authors further explored the potential mechanisms of immune escape in early-relapse HCC. They found that tumor cells in early-relapse HCC could evade the host immune system’s detection and destruction through suppressing DC-mediated antigen presentation and recruiting CD161 CD8þ T-cells. Thehigh incidence of early recurrence is themain reason for the poor clinical outcomes of HCC. Ignoring the differences between recurrent and primary tumors, recurrent HCCs are often treated based on the pathological characteristics and molecularclassificationof theprimaryHCCs.Althoughprevious studieshave reported that similar genomicalterationsoccurred inbothprimaryandearly-relapseHCCs,10whetherprimaryand early-relapse HCCs have differences in immune contexture is still unknown. The present study dissected and compared the TIME of primary and early-relapse HCCs by scRNA-seq. Unlike the findings in primary HCC reported in the previous studies (the primary HCC cells recruit Tregs to suppress the immune response8), this study found that Tregs were excluded and CD161 CD8þ T-cells were recruited to create an immunosuppressive microenvironment in early-relapse HCC. In CD161 CD8þ T-cells from recurrent tumor tissues, the expression levels of proliferationand cytotoxicity-associated