Establishment and validation of exhausted CD8+ T cell feature as a prognostic model of HCC

Abstract

ObjectivesThe exhausted CD8+T (Tex) cells are a unique cell population of activated T cells that emerges in response to persistent viral infection or tumor antigens. Tex cells showed the characteristics of aging cells, including weakened self-renewal ability, effector function inhibition, sustained high expression of inhibitory receptors including PD-1, TIGIT, TIM-3, and LAG-3, and always accompanied by metabolic and epigenetic reprogramming. Tex cells are getting more and more attention in researching immune-related diseases and tumor immunotherapy. However, studies on Tex-related models for tumor prognosis are still lacking. We hope to establish a risk model based on Tex-related genes for HCC prognosis.MethodsTex-related GEO datasets from different pathologic factors (chronic HBV, chronic HCV, and telomere shortening) were analyzed respectively to acquire differentially expressed genes (DEGs) by the ‘limma’ package of R. Genes with at least one intersection were incorporated into Tex-related gene set. GO, KEGG, and GSEA enrichment analyses were produced. Hub genes and the PPI network were established and visualized by the STRING website and Cytoscape software. Transcription factors and targeting small molecules were predicted by the TRUST and CLUE websites. The Tex-related HCC prognostic model was built by Cox regression and verified based on different datasets. Tumor immune dysfunction and exclusion (TIDE) and SubMap algorithms tested immunotherapy sensitivity. Finally, qRT-PCR and Flow Cytometry was used to confirm the bioinformatic results.ResultsHub genes such as AKT1, CDC6, TNF and their upstream transcription factor ILF3, Regulatory factor X-associated protein, STAT3, JUN, and RELA/NFKB1 were identified as potential motivators for Tex. Tex-related genes SLC16A11, CACYBP, HSF2, and ATG10 built the HCC prognostic model and helped with Immunotherapy sensitivity prediction.ConclusionOur study demonstrated that Tex-related genes might provide accurate prediction for HCC patients in clinical decision-making, prognostic assessment, and immunotherapy. In addition, targeting the hub genes or transcription factors may help to reverse T cell function and enhance the effect of tumor immunotherapy.

Systemic Pan-Caner Analysis Identifies CACYBP as a Novel Biomarker for Cancer Prognosis and Immunity

“…And some evidence indicated that CACYBP was involved in regulating TME in tumors, such as hepatocellular carcinoma, esophageal cancer and colorectal cancer [49][50][51] . CACYBP may be a promising target for cancer immunotherapy, especially for hepatocellular carcinoma [52][53][54] . In the present study, we found that CACYBP expression was negatively linked with the ESTIMATEScore, the ImmuneScore, and the StromalScore in multiple cancers.…”

The Characteristics of Transcription Factors Regulating T Cell Exhaustion Were Analyzed to Predict the Prognosis and Therapeutic Effect in Patients with HCC

“… 25 Although some scholars have conducted related studies on Tex and HCC, there is still a lack of research on the regulation of Tex transcription factors and HCC. 26 , 27 Transcription factors regulating Tex have been gradually discovered, such as IRF4, BATF, NFATc1, NR4A, TBX21, EOMES and TOX. 28–30 …”

“…25 Although some scholars have conducted related studies on Tex and HCC, there is still a lack of research on the regulation of Tex transcription factors and HCC. 26,27 Transcription factors regulating Tex have been gradually discovered, such as IRF4, BATF, NFATc1, NR4A, TBX21, EOMES and TOX. [28][29][30] IRF4 is a T-cell receptor (TCR) signal-sensitive transcription factor that interacts with BATF and NFAT to promote PDCD1 transcription.…”