Multiomics identifies the link between intratumor steatosis and the exhausted tumor immune microenvironment in hepatocellular carcinoma.
IF: 17.298
Cited by: 19


Immunotherapy has become the standard-of-care treatment for hepatocellular carcinoma (HCC), but its efficacy remains limited. To identify immunotherapy-susceptible HCC, we profiled the molecular abnormalities and tumor immune microenvironment (TIME) of rapidly increasing nonviral HCC. We performed RNA-seq of tumor tissues in 113 patients with nonviral HCC and cancer genome sequencing of 69 genes with recurrent genetic alterations reported in HCC. Unsupervised hierarchical clustering classified nonviral HCCs into three molecular classes (Class I, II, III), which stratified patient prognosis. Class I, with the poorest prognosis, was associated with TP53 mutations, whereas class III, with the best prognosis, was associated with cadherin-associated protein beta 1 (CTNNB1) mutations. Thirty-eight percent of nonviral HCC was defined as an immune class characterized by a high frequency of intratumoral steatosis and a low frequency of CTNNB1 mutations. Steatotic HCC, which accounts for 23% of nonviral HCC cases, presented an immune-enriched but immune-exhausted TIME characterized by T cell exhaustion, M2 macrophage and cancer-associated fibroblast (CAF) infiltration, high PD-L1 expression, and TGF-β signaling activation. Spatial transcriptome analysis suggested that M2 macrophages and CAFs may be in close proximity to exhausted CD8+ T cells in steatotic HCC. An in vitro study showed that palmitic acid-induced lipid accumulation in HCC cells upregulated PD-L1 expression and promoted immunosuppressive phenotypes of cocultured macrophages and fibroblasts. Patients with steatotic HCC, confirmed by chemical-shift MR imaging, had significantly longer PFS with combined immunotherapy using anti-PD-L1 and anti-VEGF antibodies. Multiomics stratified nonviral HCCs according to prognosis or TIME. We identified the link between intratumoral steatosis and immune-exhausted immunotherapy-susceptible TIME.



MeSH terms

Carcinoma, Hepatocellular
Liver Neoplasms
CD8-Positive T-Lymphocytes
Tumor Microenvironment


Murai, Hiroki
Kodama, Takahiro
Maesaka, Kazuki
Tange, Shoichiro
Motooka, Daisuke
Suzuki, Yutaka
Shigematsu, Yasuyuki
Inamura, Kentaro
Mise, Yoshihiro
Saiura, Akio
Ono, Yoshihiro
Takahashi, Yu
Kawasaki, Yota
Iino, Satoshi
Kobayashi, Shogo
Idogawa, Masashi
Tokino, Takashi
Hashidate-Yoshida, Tomomi
Shindou, Hideo
Miyazaki, Masanori
Imai, Yasuharu
Tanaka, Satoshi
Mita, Eiji
Ohkawa, Kazuyoshi
Hikita, Hayato
Sakamori, Ryotaro
Tatsumi, Tomohide
Eguchi, Hidetoshi
Morii, Eiichi
Takehara, Tetsuo

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