A systematic and comprehensive analysis of T cell exhaustion related to therapy in lung adenocarcinoma tumor microenvironment

Abstract

Background: T cell exhaustion (TEX) is an important immune escape mechanism, and an in-depth understanding of it can help improve cancer immunotherapy. However, the prognostic role of TEX in malignant lung adenocarcinoma (LUAD) remains unclear.Methods: Through TCGA and GEO datasets, we enrolled a total of 498 LUAD patients. The patients in TCGA-LUAD were unsupervised clustered into four clusters according to TEX signaling pathway. WGCNA analysis, survival random forest analysis and lasso regression analysis were used to select five differentially expressed genes among different clusters to construct a TEX risk model. The risk model was subsequently validated with GEO31210. By analyzing signaling pathways, immune cells and immune checkpoints using GSEA, GSVA and Cibersortx, the relationship between TEX risk score and these variables was evaluated. In addition, we further analyzed the expression of CCL20 at the level of single-cell RNA-seq and verified it in cell experiments.Results: According to TEX signaling pathway, people with better prognosis can be distinguished. The risk model constructed by CD109, CCL20, DKK1, TNS4, and TRIM29 genes could further accurately identify the population with poor prognosis. Subsequently, it was found that dendritic cells, CD44 and risk score were closely related. The final single-cell sequencing suggested that CCL2O is a potential therapeutic target of TEX, and the interaction between TEX and CD8 + T is closely related.Conclusion: The classification of T cell depletion plays a crucial role in the clinical decision-making of lung adenocarcinoma and needs to be further deepened.

A comprehensive meta-analysis of tissue resident memory T cells and their roles in shaping immune microenvironment and patient prognosis in non-small cell lung cancer

“…The other 8 genes, CLEC17A, FST, GNG7 ( 49 ), HSPA4 ( 38 ), LTK ( 39 ), NEFL, RDX ( 40 ), and SIK1 ( 41 ), have been associated with general immune or tumor suppression pathways ( 38 – 41 , 49 ). The correlation between immune response and some of the genes in the 18-gene list like CCL20, CD109 and CD200R1 were also identified in other studies ( 50 – 52 ). Given the significant correlations with T RM observed in the current multi-omics study, those genes related to tumor immunity and T cell interaction that have not been well-studied will be applied for future biological investigation.…”

CD109 drives pro-tumorigenic cell properties in human non-small cell lung cancer through interaction with desmoglein-2

“…Among different physiological functions such as protection of stem cells from premature differentiation 4 , detrimental properties have been described mostly linked to tumor biology 47,48 . For some tumor entities, CD109 was suggested as novel clinical biomarker 19 and for LUAD patients CD109 was identified among a cluster of risk genes in patients with poor prognosis 49 . In our study, we can now add another layer of complexity to CD109 in tumor biology of NSCLC.…”

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.…”

“…In the context of osteosarcoma, cuproptosis‐related lncRNAs may diminish Treg cell populations, enhancing the efficacy of anti‐PD‐1 antibodies 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 .…”