Novel γδ T cell-based prognostic signature to estimate risk and aid therapy in hepatocellular carcinoma

Abstract

Background Numerous studies have revealed that gamma delta (γδ) T cell infiltration plays a crucial regulatory role in hepatocellular carcinoma (HCC) development. Nonetheless, a comprehensive analysis of γδ T cell infiltration in prognosis evaluation and therapeutic prediction remains unclear. Methods Multi-omic data on HCC patients were obtained from public databases. The CIBERSORT algorithm was applied to decipher the tumor immune microenvironment (TIME) of HCC. Weighted gene co-expression network analysis (WGCNA) was performed to determine significant modules with γδ T cell-specific genes. Kaplan-Meier survival curves and receiver operating characteristic analyses were used to validate prognostic capability. Additionally, the potential role of RFESD inhibition by si-RFESD in vitro was investigated using EdU and CCK-8 assays. Results A total of 16,421 genes from 746 HCC samples (616 cancer and 130 normal) were identified based on three distinct cohorts. Using WGCNA, candidate modules (brown) with 1755 significant corresponding genes were extracted as γδ T cell-specific genes. Next, a novel risk signature consisting of 11 hub genes was constructed using multiple bioinformatic analyses, which presented great prognosis prediction reliability. The risk score exhibited a significant correlation with ICI and chemotherapeutic targets. HCC samples with different risks experienced diverse signalling pathway activities. The possible interaction of risk score with tumor mutation burden (TMB) was further analyzed. Subsequently, the potential functions of the RFESD gene were explored in HCC, and knockdown of RFESD inhibited cell proliferation in HCC cells. Finally, a robust prognostic risk-clinical nomogram was developed and validated to quantify clinical outcomes. Conclusions Collectively, comprehensive analyses focusing on γδ T cell patterns will provide insights into prognosis prediction, the mechanisms of immune infiltration, and advanced therapy strategies in HCC.

Causal Links Between Circulating Immune Traits and Hepatocellular Carcinoma: A Bi- Directional Mendelian Randomization Study

“…Moreover, T cell central memory (CM) status was associated with an increased incidence of HCC, while higher numbers of γδ T cells and double-negative T (DNT) cells were linked to a reduced risk of HCC, consistent with previous ndings [31,32]. The growing recognition of the crucial role of DNT/γδT cells in tumor immune surveillance has opened avenues for adoptive reinfusion therapies, including "off-the-shelf" options currently under investigation in clinical trials for various cancers, including HCC [33][34][35][36][37].…”

γδ T Cells: A Game Changer in the Future of Hepatocellular Carcinoma Immunotherapy

“…The proposed Vδ1 + /Vδ2 + ratio emerges as a potential indicator for clinical prognosis, with higher ratios associating with more suppressed immunity and poorer outcomes. The study also identified reduced NKG2D expression in the Vδ1 + population, suggesting depressed cell activation and enhanced survival ability, while a higher pPD1 expression in the Vδ2 + population indicated suppressed cytotoxicity [58]. These results are in alignment with the research of Wang et al, who aimed to analyze γδ T cell infiltration in HCC for prognosis and therapeutic prediction [59].…”

“…Strikingly, these immune cell infiltrations exhibited no statistical differences among different pTNM stages, affirmin g the highly immunosuppressive nature of the HCC TME across various disease stages. The authors further extended their investigation to the phenotypic profiles of circulating γδ T cells in HCC and healthy populations [58]. The analysis reveals a dominance of the Vδ2 + subset in the PB of healthy individuals, while under immune-suppressed conditions in HCC, the Vδ2 + subset is significantly depleted.…”

“…HCC transcriptomic data reveal a significant upregulation of inhibitory checkpoint molecules in HCC tissues compared to normal tissues [58]. Notably, these molecules, including CTLA4, hepatitis A virus cellular receptor 2 (HAVCR2), lymphocyte-activation gene 3 (LAG3), programmed cell death protein 1 (PDCD1), programmed cell death 1 ligand 2 (PDCD1LG2), T cell immunoreceptor with immunoglobulin (Ig) and immunoreceptor tyrosine-based inhibitory motif (ITIM) domains (TIGIT), and sialic acid-binding Ig-like lectin 15 (SIGLEC15), show consistent expression across different patient pTNM stages, suggesting a uniform responsiveness to ICB therapy.…”

Prognostic value of combined inflammatory and nutritional biomarkers in HCC within the Milan criteria after hepatectomy

“…Lymphocytes play an important role in cancer surveillance ( 35 ). Accumulating evidence supported that the interactions of infiltrating immune cells with tumor components act as vital driving factors for tumor progression and therapeutic sensitivity ( 36 , 37 ). As the prime anti-tumor cells, CD8 + T cells can secrete IFN-γ and TNFα to destroy cancerous cells once they contact tumor cells or eliminate tumor cells by releasing perforin and granzyme B through the Fas/FasL pathway ( 38 ).…”