Positive Correlation Between LTA Expression and Overall Immune Activity Suggests an Increased Probability of Survival in Uterine Corpus Endometrial Carcinoma.

Mingjie Shi,Yue Wei,Riling Chen,Fei Luo,Taotao Shao,Hengli Zhang,Runmin Guo,Taili Yang

doi:10.3389/fcell.2021.793793

Abstract

Mounting evidence indicates that immune status plays a crucial role in tumor progress and metastasis, while there are no effective and easily assayed biomarkers to reflect it in uterine corpus endometrial carcinoma (UCEC) patients. Here, we attempted to identify the potential biomarkers that were differentially expressed between normal and tumor tissues and involved in prognosis and immune microenvironment of UCEC patients. RNA-seq data with relevant clinical information were obtained from The Cancer Genome Atlas (TCGA). ssGSEA algorithm was applied to calculate the enrichment scores of every tumor infiltration lymphocyte (TIL) set in each sample, and patients were then divided into three clusters using multiple R packages. Cox analysis, ESTIMATE, and CIBERSORT were utilized to determine the differentially expressed immune-related genes (DEIGs) with overall survival, and to explore their roles in prognosis, immune microenvironment, and immunotherapeutic response. The TIMER and TISIDB databases were utilized to predict the effectiveness of immunotherapy in UCEC patients. LTA was finally identified to be significantly upregulated in tumor tissues and closely associated with prognosis and immunological status, which was then verified in GSE17025. In multivariate analysis, the hazard ratio of LTA was 0.42 with 95% CI (0.22–0.80) (p = 0.008). Patients with high LTA expression had better survival and apparently immune-activated phenotypes, such as more tumor mutation burden (TMB), stronger immune cell infiltrations, higher expression of immunosuppressive points, and higher immunophenoscore, meaning they had an immunotherapeutic advantage over those with low LTA expression. TIMER and TISIDB indicated that LTA was highly expressed in UCEC, and its expression was negatively correlated with stages and positively related to prognosis. Additionally, we found that LTA ectopic expression weakened the proliferation ability of RL95-2 cells. All these findings indicated that LTA could act as a novel and easily assayed biomarker to predict immunological status and clinical outcomes and even as an antioncogene to explore UCEC in depth.

Highlights

Uterine corpus endometrial carcinoma (UCEC) is a common malignancy in females (Bray et al, 2018)
We explored the correlations between lymphotoxin alpha (LTA) and the immune cells in TIMER, its expression was positively correlated with six types of immune cells after adjustment by tumor purity in the TIMER database, namely, B cell, CD8+ T cell, CD4+ T cell, macrophage, neutrophil, and dendritic cell (Figure 4A)
To reflect more fully the relationship between LTA and immune infiltration, we analyzed the correlations between LTA and multiple immune markers characterized by immune cells, 40 out of 45 markers were significantly correlated with LTA expression after adjusting for tumor purity, indicating the magnitude of LTA in tumor immunity regulation (Table 2)

Summary

Introduction

Uterine corpus endometrial carcinoma (UCEC) is a common malignancy in females (Bray et al, 2018). Patients with the following characteristics can be considered to have a high probability of benefiting from immunotherapy, such as microsatellite instability (Fujimoto et al, 2020), more abundance of DNA polymerase ε (POLE) mutation (Hwang et al, 2021), and higher levels of immunosuppressants targets (Paré et al, 2018). They are unsuitable as desirable markers for dynamically monitoring the immune status and prognosis of patients because of the difficulty in evaluation

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Discussion

Conclusion