Hepatocellular carcinoma (HCC) represents a paradigm of the relation between tumor microenvironment (TME) and tumor development. Here, we generate a single-cell atlas of the multicellular ecosystem of HCC from four tissue sites. We show the enrichment of central memory T cells (TCM) in the early tertiary lymphoid structures (E-TLSs) in HCC and assess the relationships between chronic HBV/HCV infection and T cell infiltration and exhaustion. We find the MMP9+ macrophages to be terminally differentiated tumor-associated macrophages (TAMs) and PPARγ to be the pivotal transcription factor driving their differentiation. We also characterize the heterogeneous subpopulations of malignant hepatocytes and their multifaceted functions in shaping the immune microenvironment of HCC. Finally, we identify seven microenvironment-based subtypes that can predict prognosis of HCC patients. Collectively, this large-scale atlas deepens our understanding of the HCC microenvironment, which might facilitate the development of new immune therapy strategies for this malignancy.

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Hepatocellular carcinoma (HCC) is one of the most common cancers worldwide. In China, chronic hepatitis B virus (HBV) infection remains the major risk factor for HCC. In this study, we performed a genome-wide association study (GWAS) among Chinese populations to identify novel genetic loci contributing to susceptibility to HBV-related HCC. GWAS scan is performed in a collection of 205 HBV-related HCC trios (each trio includes an affected proband and his/her both parents), and 355 chronic HBV carriers with HCC (cases) and 360 chronic HBV carriers without HCC (controls), followed by two rounds of replication studies totally consisting of 3,796 cases and 2,544 controls. We identified a novel association signal within the gene at 7q21.13 (index rs10272859, OR = 1.28, = 9.46 × 10). Furthermore, we observed that the at-risk rs10272859[G] allele was significantly associated with higher mRNA expression levels of in liver tissues. Chromosome conformation capture assays in liver cells confirmed that a physical interaction exists between the promoter region of and the risk-associated SNPs in strong linkage disequilibrium with the index rs10272859 at 7q21.13. This index rs10272859 also showed significant association with the survival of HCC patients. Our findings highlight a novel locus at 7q21.13 conferring both susceptibility and prognosis to HBV-related HCC, and suggest the gene to be the functional target of the 7q21.13 locus..

Hepatocellular carcinomas (HCCs) are characterized by frequent somatic genomic copy number alterations (CNAs), with most of them biologically unexplored. Here, we performed integrative analyses combining CNAs with the transcriptomic data to reveal the cis- and trans-effects of CNAs in HCC. We identified recurrent genomic gains of chromosome 8q, which exhibit strong trans-effects and are broadly associated with ribosome biogenesis activity. Furthermore, 8q gain–driven overexpression of ribosome biogenesis regulator (RRS1) promotes growth of HCC cells in vitro and in vivo. Mechanistically, RRS1 attenuates ribosomal stress through retaining RPL11 in the nucleolus, which, in turn, potentiates MDM2-mediated ubiquitination and degradation of p53. Clinically, higher RRS1 expression levels predict poor clinical outcomes for patients with HCC, especially in those with intact p53. Our findings established that the chromosome 8q oncogene RRS1 promotes HCC development through attenuating the RPL11-MDM2-p53 pathway and provided new potential targets for treatment of this malignancy.