The presence of vessels encapsulating tumor clusters is associated with an immunosuppressive tumor microenvironment in hepatocellular carcinoma

Abstract

Recently, a distinct vascular pattern in hepatocellular carcinoma (HCC) called vessels encapsulating tumor‐forming clusters (VETC) has received attention because of its association with poor prognosis. However, little is known about the mechanism by which VETC promotes an aggressive phenotype at the molecular level. In our study, the association between differences in stepwise signal intensity in the HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment were investigated using the International Cancer Genome Consortium (ICGC) cohort (66 patients). To our knowledge, this is the first study to analyze the molecular patterns of VETC using RNA‐Seq data. The VETC+ HCC group showed significantly lower overall survival and higher cumulative incidence of extrahepatic metastasis after curative hepatic resection than the VETC− HCC group. The VETC+ group exhibited molecular features indicative of lower immune activation than the VETC− group, suggesting that tumor cells in the VETC+ group were more likely to escape from the immune response, which could lead to the shorter OS (Overall survival) and higher risk of metastasis. On the other hand, gene expression levels of fibroblast growth factor receptors were upregulated in VETC+ HCC, suggesting that VETC+ HCC might benefit from lenvatinib treatment. Our results demonstrate that VETC+ HCC was associated with the suppression of tumor immune responses at the molecular level.

Potential involvement of oncostatin M in the immunosuppressive tumor immune microenvironment in hepatocellular carcinoma with vessels encapsulating tumor clusters

“…11 In the present study, the Previous studies have revealed that VETC-positive HCC has fewer tumor-infiltrating CD3-positive cells than VETC-negative HCC, 29 and their transcriptional analysis shows molecular characteristics indicative of lower immune activation. 16 Likewise, the majority of VETC-positive HCC cases are categorized into the immune-low/angiogenic immunovascular subtype. 17 In the present study, we observed that the number of CD8-positive cells was significantly lower in VETC-positive HCC than that in VETCnegative HCC, which is consistent with the previous studies, 16,17 suggesting that VETC-positive HCC cells are more likely to escape from immune attacks.…”

“…16 Likewise, the majority of VETC-positive HCC cases are categorized into the immune-low/angiogenic immunovascular subtype. 17 In the present study, we observed that the number of CD8-positive cells was significantly lower in VETC-positive HCC than that in VETCnegative HCC, which is consistent with the previous studies, 16,17 suggesting that VETC-positive HCC cells are more likely to escape from immune attacks. The reduction in tumor-infiltrating CD8positive cells is indicative of an adverse prognostic factor, [30][31][32] which potentially contributes to the poor prognosis associated Interestingly, we found that background liver cirrhosis was negatively associated with the presence of VETC.…”

“…Indeed, recent transcriptomic analyses have demonstrated that HCCs with the VETC pattern (VETC-positive HCCs) are characterized by reduced activation of immune cells compared with HCCs without the VETC pattern (VETCnegative HCC). 16,17 However, the underlying factors characterizing the tumor cells and tumor immune microenvironment (TIM) of VETCpositive HCC remain poorly understood.…”

Correlations behind macrotrabecular‐massive and vessels encapsulating tumor cluster patterns in hepatocellular carcinoma

“…VETC and MTM patterns are primarily represented by IL/AG subtypes. Zhang et al [33] used RNAseq data to analyze molecular patterns in the VETC+ and VETC− groups. This analysis detected an increased enrichment of mRNAs associated with an efficient immune response in the VETC+ group.…”

“…This analysis detected an increased enrichment of mRNAs associated with an efficient immune response in the VETC+ group. Thus, it appears that tumors evade the immune system because of a molecular feature that inhibits normal responses of the immune system to tumor cells [33]. These results suggest that the immunosuppressive microenvironment of HCC may affect the formation of MTM and VETC patterns.…”