Cuproptosis regulator-mediated patterns associated with immune infiltration features and construction of cuproptosis-related signatures to guide immunotherapy

Abstract

BackgroundLiver hepatocellular carcinoma (HCC) is a prevalent cancer that lacks a sufficiently efficient approach to guide immunotherapy. Additionally, cuproptosis is a recently identified regulated cell death program that is triggered by copper ionophores. However, its possible significance in tumor immune cell infiltration is still unclear.MethodsCuproptosis subtypes in HCC were identified using unsupervised consensus cluster analysis based on 10 cuproptosis regulators expressions, and a cuproptosis-related risk signature was generated using univariate and LASSO Cox regression and validated using the ICGC data. Moreover, the relationship between signature and tumor immune microenvironment (TME) was studied through tumor immunotherapy responsiveness, immune cell infiltration, and tumor stem cell analysis. Finally, clinical specimens were analyzed using immunohistochemistry to verify the expression of the three genes in the signature.ResultsTwo subtypes of cuproptosis regulation were observed in HCC, with different immune cell infiltration features. Genes expressed differentially between the two cuproptosis clusters in the TCGA were determined and used to construct a risk signature that was validated using the ICGC cohort. Greater immune and stromal cell infiltration were observed in the high-risk group and were associated with unfavorable prognosis. Elevated risk scores were linked with higher RNA stemness scores (RNAss) and tumor mutational burden (TMB), together with a greater likelihood of benefitting from immunotherapy.ConclusionIt was found that cuproptosis regulatory patterns may play important roles in the heterogeneity of immune cell infiltration. The risk signature associated with cuproptosis can assess each patient’s risk score, leading to more individualized and effective immunotherapy.

A cuproptosis random forest cox score model-based evaluation of prognosis, mutation characterization, immune infiltration, and drug sensitivity in hepatocellular carcinoma

“…Since the discovery of cuproptosis, the role of cuptoptosis in liver cancer prognosis and TME has been gradually evaluated. Previous studies mainly explored this issue by constructing Lasso cox model, which directly entered the target genes as model inputs (47)(48)(49)(50)(51)(52)(53). The Lasso model is applied to analyze multicollinearity data (54).…”

“…Next, we assessed the drug-sensitivity of CRFCS in HCC by applying the R package of "pRRophetic". By analyzing data from TCGA, we found that the high CRFCS group had a lower IC 50 sorafenib compared with the low CRFCS group (Figure 6A). To verify these results, an external data from ICGC-LIHC-US was analyzed which confirmed that the high CRFCS group are more sensitive to sorafenib (Figure 6B).…”

A comprehensive analysis focusing on cuproptosis to investigate its clinical and biological relevance in uterine corpus endometrial carcinoma and its potential in indicating prognosis

“…It leads to the aggregation of lipoacylated proteins and the loss of iron-sulfur cluster proteins, which may ultimately result in cell death due to toxic effects ( Tsvetkov et al, 2022 ). These findings suggest a novel perspective for investigating the application of cuproptosis in cancer treatment ( Wang et al, 2022a ).…”

Ferroptosis and cuproptosis prognostic signature for prediction of prognosis, immunotherapy and drug sensitivity in hepatocellular carcinoma: development and validation based on TCGA and ICGC databases

“…We compared our own model to 12 other published HCC prognostic models to better show its predictive power (20)(21)(22)(23)(24)(25)(26)(27)(28)(29)(30)(31). Multivariate analysis was used to calculate the risk value and prognostic evaluation for each dataset, leveling the playing field amongst the four models.…”