CD8+ T cell trajectory subtypes decode tumor heterogeneity and provide treatment recommendations for hepatocellular carcinoma

Abstract

IntroductionMounting evidence has revealed that the interactions and dynamic alterations among immune cells are critical in shaping the tumor microenvironment and ultimately map onto heterogeneous clinical outcomes. Currently, the underlying clinical significance of immune cell evolutions remains largely unexplored in hepatocellular carcinoma (HCC).MethodsA total of 3,817 immune cells and 1,750 HCC patients of 15 independent public datasets were retrieved. The Seurat and Monocle algorithms were used to depict T cell evolution, and nonnegative matrix factorization (NMF) was further applied to identify the molecular classification. Subsequently, the prognosis, biological characteristics, genomic variations, and immune landscape among distinct clusters were decoded. The clinical efficacy of multiple treatment approaches was further investigated.ResultsAccording to trajectory gene expression, three heterogeneous clusters with different clinical outcomes were identified. C2, with a more advanced pathological stage, presented the most dismal prognosis relative to C1 and C3. Eight independent external cohorts validated the robustness and reproducibility of the three clusters. Further explorations elucidated C1 to be characterized as lipid metabolic HCC, and C2 was referred to as cell-proliferative HCC, whereas C3 was defined as immune inflammatory HCC. Moreover, C2 also displayed the most conspicuous genomic instability, and C3 was deemed as “immune-hot”, having abundant immune cells and an elevated expression of immune checkpoints. The assessments of therapeutic intervention suggested that patients in C1 were suitable for transcatheter arterial chemoembolization treatment, and patients in C2 were sensitive to tyrosine kinase inhibitors, while patients in C3 were more responsive to immunotherapy. We also identified numerous underlying therapeutic agents, which might be conducive to clinical transformation in the future.ConclusionsOur study developed three clusters with distinct characteristics based on immune cell evolutions. For specifically stratified patients, we proposed individualized treatment strategies to improve the clinical outcomes and facilitate the clinical management.

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

“…Whereas the low-risk patients were mainly a metabolic subtype which was correlated with oxidoreductase activity, cytochrome P450-induced metabolism and numerous endogenous metabolism. Our study was consistent with the previous studies ( Chen et al, 2020 ) ( Liu et al, 2022 ). The study by Liu et al identified three heterogeneous clusters based on immune cell evolutions, with proliferative HCC a more advanced pathological stage and dismal prognosis relative to lipid metabolic and immune inflammatory tumors ( Liu et al, 2022 ).…”

“…Our study was consistent with the previous studies ( Chen et al, 2020 ) ( Liu et al, 2022 ). The study by Liu et al identified three heterogeneous clusters based on immune cell evolutions, with proliferative HCC a more advanced pathological stage and dismal prognosis relative to lipid metabolic and immune inflammatory tumors ( Liu et al, 2022 ). Another study by Chen et al divided HCC according to energy metabolism genes, observing a positive correlation of a metabolism-enriched subtype with better survival ( Chen et al, 2020 ).…”

“…Tumors with proliferative characteristics were more sensitive to conventional chemotherapeutics, whereas those with metabolic characteristics were susceptible to tyrosine kinase inhibitors such as lapatinib and erlotinib. Our results were consistent with the study by Liu et al, where they identified obatoclax, docetaxel, and cisplatin as potential therapeutic agents for tumors in proliferative clusters, whereas recommended nilotinib and bosutinib for tumors in lipid metabolic clusters ( Liu et al, 2022 ). According to the study by Li et al, HMGA1 promotes the proliferation of liver cancer via regulating the Akt signaling pathway ( Liu et al, 2017 ).…”

“…Our study was consistent with the previous studies (Chen et al, 2020) (Liu et al, 2022). The study by Liu et al identified three heterogeneous clusters based on immune cell evolutions, with proliferative HCC a more advanced pathological stage and dismal prognosis relative to lipid metabolic and immune inflammatory tumors (Liu et al, 2022).…”

Epigenetically regulated gene expression profiles decipher four molecular subtypes with prognostic and therapeutic implications in gastric cancer

“…In addition, to confirm the stability of the ssGSEA results, the remaining six immune cell infiltration assessment methods (including EPIC, ESTIMATE, MCPcounter, Quantiseq, TIMER, and xCell) were further performed [ 24 ]. Apart from that, to explore the expression differences of immune checkpoints (ICPs) for different subtypes, the expression of 27 ICPs including TNF family, B7 family, and other molecules for each sample were extracted from the TCGA cohort [ 25 – 27 ].…”