CD8+ T Cell-Associated Gene Signature Correlates With Prognosis Risk and Immunotherapy Response in Patients With Lung Adenocarcinoma

Zhang, Minghui; Ma, Jianying; Guo, Qinyue; Ding, Shuang; Wang, Yan; Pu, Haihong

doi:10.3389/fimmu.2022.806877

Cited by 20 publications

(20 citation statements)

References 54 publications

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“…established a CD8 + T cell-associated gene signature, which could help assess prognostic risk and immunotherapy response in LUAD patients. However, they did not validate the signature with real-world samples ( 66 ). Moreover, some researchers demonstrated the tumor immune microenvironment by analyzing the targeted RNA-Seq of immune-related genes, which had prognostic value for locally advanced LUAD ( 67 ).…”

Section: Discussionmentioning

confidence: 97%

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

Feng

Xu²,

Zhang³

et al. 2022

Front. Immunol.

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Patients with stage III lung adenocarcinoma (LUAD) have significant survival heterogeneity, meanwhile, CD8+ T cell has a remarkable function in immunotherapy. Therefore, developing novel biomarkers based on CD8+ T cell can help evaluate the prognosis and guide the strategy of immunotherapy for patients with stage III LUAD. Thus, we abstracted twelve datasets from multiple online databases and grouped the stage III LUAD patients into training and validation sets. We then used WGCNA and CIBERSORT, while univariate Cox analysis, LASSO analysis, and multivariate Cox analysis were performed. Subsequently, a novel CD8+ T cell-related classifier including HDFRP3, ARIH1, SMAD2, and UPB1 was developed, which could divide stage III LUAD patients into high- and low-risk groups with distinct survival probability in multiple cohorts (all P < 0.05). Moreover, a robust nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its powerful predictive capacity. Besides, we detected the difference in immune cell subpopulations and evaluated the potential benefits of immunotherapy between the two risk subsets. Finally, we verified the correlation between the gene expression and CD8+ T cells included in the model by immunohistochemistry and validated the validity of the model in a real-world cohort. Overall, we constructed a robust CD8+ T cell-related risk model originally which could predict the survival rates in stage III LUAD. What’s more, this model suggested that patients in the high-risk group could benefit from immunotherapy, which has significant implications for accurately predicting the effect of immunotherapy and evaluating the prognosis for patients with stage III LUAD.

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Section: Discussionmentioning

confidence: 97%

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

Feng

Xu²,

Zhang³

et al. 2022

Front. Immunol.

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“…The underlying mechanism perhaps related to TGFβ1-induced autophagy relying on expression of SMAD4. In SMAD4-negative PDAC cells, TGFB1-induced autophagy triggers the expression of MAPK/ERK, giving rise to migration rather than proliferation, which accounts for metastasis (27). We further analyzed relation between SMAD4 and local recurrence as well as distant metastasis.…”

Section: Discussionmentioning

confidence: 99%

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

Song

Ding

et al. 2023

Front. Med.

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ObjectivesIn malignant tumors, elevated infiltration of intratumoral CD8+ cytotoxic T cells predicts a beneficial prognosis, whereas high levels of CD15+ neutrophils in peritumor tissues indicate poor prognosis. It is unclear how SMAD4, which promotes favorable clinical outcomes and antitumor immunoregulation, along with CD8+ cytotoxic T cells and CD15+ neutrophils exert an influence on hypopharyngeal carcinoma (HPC).Materials and methodsSpecimens were collected from 97 patients with HPC. Immunohistological analyses of SMAD4, CD8+ cytotoxic T cell and CD15+ neutrophil expression were performed. SMAD4 nuclear intensity was measured, meanwhile, CD8+ cytotoxic T cells and CD15+ neutrophils were counted under a microscope. The prognostic role of SMAD4 was determined using the log-rank test and univariate and multivariate analyses. The relationship among SMAD4, CD8+ cytotoxic T cells, and CD15+ neutrophils was estimated by Mann–Whitney U test.ResultsHigh levels of SMAD4 were associated with favorable overall survival (OS) and disease-free survival (DFS) in HPC. Multivariate analysis suggested that SMAD4 is an independent predictor of OS and DFS. A high density of intratumoral CD8+ cytotoxic T cells and low accumulation of CD15+ neutrophils in the peritumor area were associated with longer OS and DFS. Furthermore, SMAD4 was linked to the levels of intratumoral CD8+ cytotoxic T cells and peritumoral CD15+ neutrophils. Patients with high SMAD4/high intratumoral CD8+ cytotoxic T cells or high SMAD4/low peritumoral CD15+ neutrophils showed the best prognosis.ConclusionSMAD4, CD8+ cytotoxic T cell level, and CD15+ neutrophil level have prognostic value in HPC. SMAD4 is a promising prognostic marker reflecting immune response in HPC.

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“…The prediction accuracy for survival between the established PSMC signature and seven other risk signatures ( Zhang C. et al, 2020 ; Al-Dherasi et al, 2021 ; Liu L-P. et al, 2021 ; Fan et al, 2021 ; Li et al, 2022 ; Zhang et al, 2022 ; Zhu et al, 2022 ) was compared. The risk score for each signature was calculated based on the formula retrieved from the articles; these formulas are presented in Supplementary Table S1 .…”

Section: Methodsmentioning

confidence: 99%

Pan-cancer analysis identifies proteasome 26S subunit, ATPase (PSMC) family genes, and related signatures associated with prognosis, immune profile, and therapeutic response in lung adenocarcinoma

et al. 2023

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Background: Proteasome 26S subunit, ATPase gene (PSMC) family members play a critical role in regulating protein degradation and are essential for tumor development. However, little is known about the integrative function and prognostic significance of the PSMC gene family members in lung cancer.Methods: First, we assessed the expression and prognostic features of six PSMC family members in pan-cancer from The Cancer Genome Atlas (TCGA) dataset. Hence, by focusing on the relationship between PSMC genes and the prognostic, genomic, and tumor microenvironment features in lung adenocarcinoma (LUAD), a PSMC-based prognostic signature was established using consensus clustering and multiple machine learning algorithms, including the least absolute shrinkage and selection operator (LASSO) Cox regression, CoxBoost, and survival random forest analysis in TCGA and GSE72094. We then validated it in three independent cohorts from GEO and estimated the correlation between risk score and clinical features: genomic features (alterations, tumor mutation burden, and copy number variants), immune profiles (immune score, TIDE score, tumor-infiltrated immune cells, and immune checkpoints), sensitivity to chemotherapy (GDSC, GSE42127, and GSE14814), and immunotherapy (IMvigor210, GSE63557, and immunophenoscore). Twenty-one patients with LUAD were included in our local cohort, and tumor samples were submitted for evaluation of risk gene and PD-L1 expression.Results: Nearly all six PSMC genes were overexpressed in pan-cancer tumor tissues; however, in LUAD alone, they were all significantly correlated with overall survival. Notably, they all shared a positive association with increased TMB, TIDE score, expression of immune checkpoints (CD276 and PVR), and more M1 macrophages but decreased B-cell abundance. A PSMC-based prognostic signature was established based on five hub genes derived from the differential expression clusters of PSMC genes, and it was used to dichotomize LUAD patients into high- and low-risk groups according to the median risk score. The area under the curve (AUC) values for predicting survival at 1, 3, and 5 years in the training cohorts were all >.71, and the predictive accuracy was also robust and stable in the GSE72094, GSE31210, and GSE13213 datasets. The risk score was significantly correlated with advanced tumor, lymph node, and neoplasm disease stages as an independent risk factor for LUAD. Furthermore, the risk score shared a similar genomic and immune feature as PSMC genes, and high-risk tumors exhibited significant genomic and chromosomal instability, a higher TIDE score but lower immune score, and a decreased abundance of B and CD8+ T cells. Finally, high-risk patients were suggested to be less sensitive to immunotherapy but had a higher possibility of responding to platinum-based chemotherapy. The LUAD samples from the local cohort supported the difference in the expression levels of these five hub genes between tumor and normal tissues and the correlation between the risk score and PD-L1 expression.Conclusion: Overall, our results provide deep insight into PSMC genes in LUAD, especially the prognostic effect and related immune profile that may predict therapeutic responses.

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CD8+ T Cell-Associated Gene Signature Correlates With Prognosis Risk and Immunotherapy Response in Patients With Lung Adenocarcinoma

Cited by 20 publications

References 54 publications

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

A robust CD8+ T cell-related classifier for predicting the prognosis and efficacy of immunotherapy in stage III lung adenocarcinoma

The effect of SMAD4 on the prognosis and immune response in hypopharyngeal carcinoma

Pan-cancer analysis identifies proteasome 26S subunit, ATPase (PSMC) family genes, and related signatures associated with prognosis, immune profile, and therapeutic response in lung adenocarcinoma

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