Cuproptosis-related molecular subtypes direct T cell exhaustion phenotypes and therapeutic strategies for patients with lung adenocarcinoma

Abstract

Background: T cell exhaustion (TEX) heterogeneity leads to unfavorable immunotherapeutic responses in patients with cancer. Classification of TEX molecular phenotypes is pivotal to overcoming TEX and improving immunotherapies in the clinical setting. Cuproptosis is a novel form of programmed cell death associated with tumor progression. However, the relation between cuproptosis-related genes (CuRGs) and the different TEX phenotypes has not been investigated in lung adenocarcinoma (LUAD).Methods: Unsupervised hierarchical clustering and principal component analysis (PCA) algorithm were performed to determine CuRGs-related molecular subtypes and scores for patients with LUAD. The tumor immune microenvironment (TIME) landscape in these molecular subtypes and scores was estimated using ESTIMATE and ssGSEA algorithms. Furthermore, TEX characteristics and phenotypes were evaluated in distinct molecular subtypes and scores through GSVA and Spearman correlation analysis. Finally, TIDE scores, immunophenoscore, pRRophetic, GSE78220, and IMvigor210 datasets were employed to appraise the distinguishing capacity of CuRGscore in immunotherapy and pharmacotherapy effectiveness.Results: We identified three CuRGclusters, three geneClusters, and CuRGscore based on 1012 LUAD transcriptional profiles from five datasets. Compared with other molecular subtypes, CuRGcluster B, geneCluster C, and low-CuRGscore group with good prognosis presented fewer TEX characteristics, including immunosuppressive cells infiltration and TEX-associated gene signatures, signal pathways, checkpoint genes, transcription and inflammatory factors. These molecular subtypes were also responsive in distinguishing TEX phenotype in the terminal, GZMK+, and OXPHOS- TEX subtypes, but not the TCF7+ TEX subtype. Notably, copper importer and exporter, SLC31A1 and ATP7B, were remarkably associated with four TEX phenotypes and nine checkpoint genes such as PDCD1, CTLA4, HAVCR2, TIGIT, LAG3, IDO1, SIGLEC7, CD274, PDCD1LG2, indicating that cuproptosis was involved in the development of TEX and immunosuppressive environment in patients with LUAD. Moreover, CuRGscore was significantly related to the TIDE score, immunophenoscore, and terminal TEX score (Spearman R = 0.62, p < 0.001) to effectively predict immunotherapy and drug sensitivity in both training and external validation cohorts.Conclusion: Our study demonstrated the extensive effect of cuproptosis on TEX. CuRGs-related molecular subtypes and scores could illuminate the heterogeneity of TEX phenotype as reliable tools in predicting prognosis and directing more effective immunotherapeutic and chemotherapeutic strategies for patients with LUAD.

Identification and Validation of T-Cell Exhaustion Signature for Predicting Prognosis and Immune Response in Pancreatic Cancer by Integrated Analysis of Single-Cell and Bulk RNA Sequencing Data

“…TEX-related genes can be extracted from CD8TEX cells from the scRNA-seq database. Additionally, TEX-based gene signatures have been widely used to predict prognostic, molecular, and immune features, as well as therapeutic responses in several tumors, including LIHC, lung adenocarcinoma, and NSCLC [ 34 , 35 , 36 , 37 ]. In this study, we identified and validated a TEX-related signature for predicting the prognosis and immune response in PACA using integrated analysis of scRNA-seq and bulk RNA sequencing data.…”

The roles of essential trace elements in T cell biology

“… 86 In addition, cuproptosis‐related genes (CRGs) may influence T cell exhaustion phenotype and serve as effective prognostic indicators for lung adenocarcinoma. 87 In Temporal lobe epilepsy, upregulated CRGs may promote peripheral CD4 + and CD8 + T cell infiltration into epileptic focus, which increases seizure frequency. 88 In patients with pancreatic adenocarcinoma, CRGs may drive the infiltration of antitumor components, such as activated CD4 + and CD8 + T cells, which are associated with longer survival.…”