T-cell exhaustion signatures characterize the immune landscape and predict HCC prognosis via integrating single-cell RNA-seq and bulk RNA-sequencing

Abstract

BackgroundHepatocellular carcinoma (HCC), the third most prevalent cause of cancer-related death, is a frequent primary liver cancer with a high rate of morbidity and mortality. T-cell depletion (TEX) is a progressive decline in T-cell function due to continuous stimulation of the TCR in the presence of sustained antigen exposure. Numerous studies have shown that TEX plays an essential role in the antitumor immune process and is significantly associated with patient prognosis. Hence, it is important to gain insight into the potential role of T cell depletion in the tumor microenvironment. The purpose of this study was to develop a trustworthy TEX-based signature using single-cell RNA-seq (scRNA-seq) and high-throughput RNA sequencing, opening up new avenues for evaluating the prognosis and immunotherapeutic response of HCC patients.MethodsThe International Cancer Genome Consortium (ICGC) and The Cancer Genome Atlas (TCGA) databases were used to download RNA-seq information for HCC patients. The 10x scRNA-seq. data of HCC were downloaded from GSE166635, and UMAP was used for clustering descending, and subgroup identification. TEX-related genes were identified by gene set variance analysis (GSVA) and weighted gene correlation network analysis (WGCNA). Afterward, we established a prognostic TEX signature using LASSO-Cox analysis. External validation was performed in the ICGC cohort. Immunotherapy response was assessed by the IMvigor210, GSE78220, GSE79671, and GSE91061cohorts. In addition, differences in mutational landscape and chemotherapy sensitivity between different risk groups were investigated. Finally, the differential expression of TEX genes was verified by qRT-PCR.Result11 TEX genes were thought to be highly predictive of the prognosis of HCC and substantially related to HCC prognosis. Patients in the low-risk group had a greater overall survival rate than those in the high-risk group, according to multivariate analysis, which also revealed that the model was an independent predictor of HCC. The predictive efficacy of columnar maps created from clinical features and risk scores was strong.ConclusionTEX signature and column line plots showed good predictive performance, providing a new perspective for assessing pre-immune efficacy, which will be useful for future precision immuno-oncology studies.

Prognostic and immunotherapeutic implications of bilirubin metabolism‐associated genes in lung adenocarcinoma

“…Consequently, we evaluated the prognostic significance of BMAG risk signature concerning ICB. The IMvigor210 cohort, comprising 348 patients, exhibited varying responses to anti‐PD‐L1 receptor inhibitors and included complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD) 20 . BMAG scores of patients with SD/PD were higher than those with CR/PR (Figure 4B).…”

“…The use of ICB has shown significant clinical success in immunotherapy targeting checkpoint proteins, such as PD‐L1 on tumour cells and PD‐1 on T cells, to enhance antitumor immunity 18 . Blocking the PD‐L1 and PD‐1 interaction with immune checkpoint inhibitors, such as anti‐PD‐1 and CTLA‐4, allows T cells to recognize and effectively eliminate tumour cells 19,20 . Here, we discovered that patients in the low‐risk group derived significant clinical benefits and extended overall survival than those in the high‐risk group, particularly among early‐stage patients.…”

“…18 Blocking the PD-L1 and PD-1 interaction with immune checkpoint inhibitors, such as anti-PD-1 and CTLA-4, allows T cells to recognize and effectively eliminate tumour cells. 19,20 Here, we discovered that patients in the low-risk group derived significant clinical benefits and extended overall survival than those in the high-risk group, particularly among earlystage patients. This finding highlights the potential value of the BMAG risk score in identifying patients more likely to respond favourably to anti-PD-1 and CTLA-4 therapy, which could ultimately improve treatment outcomes and minimize unnecessary side effects.…”

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy

“…Exhausted T cells generally exhibit dysfunctional mitochondria and decreased mitochondrial mass. Notably, they also exhibit gene signatures that have been correlated with poor prognosis in hepatocellular carcinoma patients, but also represent therapeutic targets ( 233 ). Moreover, inhibitory receptors like PD1 and CTLA4 also impair T-cell metabolism.…”

Alterations of the gut microbiota associated with the occurrence and progression of viral hepatitis

“…It could control the viral infection; however, the long-lasting inflammation could lead to hepatic damage ( Hou et al., 2018 ). Thus, the immune responses are critical for determining the outcome of hepatitis virus infection ( Su et al., 2022a ; Chi et al., 2023 ). The gut microbiota is the largest population of microorganisms in the human body.…”