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. 2021 Jul;9(13):1057.
doi: 10.21037/atm-21-36.

Low expression of IL6R predicts poor prognosis for lung adenocarcinoma

Gaofeng Sun  1   2 , Tianyi Wang  1   2 , Muqi Shi  3 , Hao Zhou  1   2 , Jinjie Wang  1   2 , Zhanghao Huang  1   2 , Haijian Zhang  4 , Jiahai Shi  1   2
Affiliations

Low expression of IL6R predicts poor prognosis for lung adenocarcinoma

Gaofeng Sun et al. Ann Transl Med. 2021 Jul.

Abstract

Background: Interleukin 6 (IL6) is both a pleiotropic cytokine and an immune-related gene. Interleukin 6 receptor (IL6R) is the receptor for IL6. It may be closely connected to the development of lung cancer. This research aims to explore the prognostic value of IL6R and prevent overtreatment of patients with lung adenocarcinoma (LUAD).

Methods: In this study, the expression of IL6R in tumor tissues and surrounding tissues was first analyzed by immunohistochemistry in the Affiliated Hospital of Nantong University (NTU) cohort. Secondly, we downloaded information from The Cancer Genome Atlas (TCGA) for the TCGA cohort and used this information to explore the messenger RNA (mRNA) level of IL6R. We then used Kaplan-Meier survival analyses, univariate and multivariate Cox analyses, nomogram models, and decision curve analyses to assess the prognostic value of IL6R. In addition, we also analyzed immune cell infiltration and the signaling pathways related to IL6R through Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG), and Gene Set Enrichment Analysis (GSEA).

Results: Through the data analysis of the NTU cohort and the TCGA cohort, it was found that the expression of IL6R in normal tissues around the tumor was higher than that in tumor tissue, and was positively correlated with the overall survival (OS) of LUAD patients. Additionally, low expression of IL6R was found to be an independent predictor of poor prognosis among the patients in these two research cohorts. Next, using GO, KEGG, and GSEA analyses, we found that partially infiltrated tumor immune cells might be related to earlier staging and better prognosis of patients with LUAD. Finally, the study of the 3-5-year survival rate of LUAD patients through the nomogram showed that the expression of IL6R could improve the accuracy of prediction to prevent the overtreatment of some LUAD patients.

Conclusions: In summary, our study indicated that the low expression of IL6R was associated with poor prognosis among LUAD patients and that low expression of IL6R is a potential independent risk factor that could provide a basis for strengthening postoperative classification management of such patients.

Keywords: Interleukin 6 receptor (IL6R); Kyoto Encyclopedia of Genes and Genomes (KEGG); lung adenocarcinoma (LUAD); prognosis; risk factor.

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Conflict of interest statement

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/atm-21-36). The authors have no conflicts of interest to declare.

Figures

Figure 1
Figure 1
The expression level of interleukin 6 receptor (IL6R) in lung adenocarcinoma (LUAD) and normal tissue samples and Kaplan-Meier survival plots of LUAD patients. (A) Representative images of IL6R IHC were taken at 5× (top) and 20× (bottom) magnifications. The scale bars are marked in the lower right corner of the image; (B) IL6R mRNA levels in the tumor and surrounding tissues of The Cancer Genome Atlas (TCGA) cohort; (C) IL6R mRNA levels in the paired samples of TCGA cohort; (D) the staining intensity of IL6R IHC in the tumor and adjacent tissues of the Affiliated Hospital of Nantong University (NTU) cohort; (E,F) the survival curve of the high and low expression of IL6R in 500 LUAD patients in TCGA cohort and the survival curve of the high and low expression of IL6R in 140 LUAD patients in the NTU cohort.
Figure 2
Figure 2
The relationship between interleukin 6 receptor (IL6R) expression and clinical parameters in patients with lung adenocarcinoma (LUAD) in the univariate and multivariate analyses and its influence on the overall survival of patients. (A) Single factor analysis and (B) multivariate analysis of the relationship between IL6R expression and clinical parameters in LUAD patients in TCGA cohort; (C) the relationship between IL6R expression and various clinical parameters; (D,E,F,G,H,I) survival curves of LUAD patients with different clinical parameters and high and low expression of IL6R.
Figure 3
Figure 3
Single-factor and multivariate analyses of the relationship between interleukin 6 receptor (IL6R) expression and clinical parameters in lung adenocarcinoma (LUAD) patients and its impact on the overall survival of patients. (A) Single-factor and (B) multivariate analyses of the relationship between IL6R expression and clinical parameters in LUAD patients in the NTU cohort; (C) the relationship between IL6R and various clinical parameters; (D,E,F) survival curves of LUAD patients with different clinical parameters and high and low expression of IL6R.
Figure 4
Figure 4
The prognostic nomogram of lung adenocarcinoma (LUAD) patients based on The Cancer Genome Atlas (TCGA) cohort and NTU cohort data. (A) Generated prognostic nomogram combining IL6R expression (mRNA level) and other risk factors (including gender, age, and TNM stage) from TCGA cohort to predict the clinical outcome of LUAD patients; (B) generated prognostic nomogram that integrates IL6R expression (IHC staining) and other risk factors (including smoking status, gender, age, and TNM stage) from the NTU cohort to predict the clinical outcome of LUAD patients; (C,D) prognostic nomogram calibration curves for 3-year (C) and 5-year (D) survival rates. The gray line represents the ideal model, and the vertical line represents the 95% confidence interval; (E,F) prognostic nomogram calibration curves for 3-year (E) and 5-year (F) survival rates. The gray line represents the ideal model, and the vertical line represents the 95% confidence interval.
Figure 5
Figure 5
Change ratio of 21 immune cell subtypes in tumor samples in the high and low interleukin 6 receptor (IL6R) expression groups.
Figure 6
Figure 6
The relationship between interleukin 6 receptor (IL6R) expression-related immune cells and the prognosis of lung adenocarcinoma (LUAD) patients. (A) The relationship between the expression level of M0 macrophages and the prognosis of patients with LUAD; (B) the relationship between the expression level of resting dendritic cells and the prognosis of patients with LUAD.
Figure 7
Figure 7
The relationship between interleukin 6 receptor (IL6R) expression-related tumor-infiltrating immune cells and clinical parameters in patients with lung adenocarcinoma (LUAD).
Figure 8
Figure 8
The differential expression of EGFR and KRAS in lung adenocarcinoma (LUAD) patients in the high and low interleukin 6 receptor (IL6R) expression group and its effects on the OS of LUAD patients. (A) The differential expression of EGFR; (B) the differential expression of KRAS; (C) effects of EGFR on OS of patients with LUAD in high and low IL6R expression groups; (D) effects of KRAS on OS of patients with LUAD in high and low IL6R expression groups.
Figure 9
Figure 9
Gene Ontology (GO), Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analysis, and Gene Set Enrichment Analysis (GSEA) of differentially expressed immune-related genes (DEIRGs). (A) GO analysis of DEIRGs; (B) KEGG pathway enrichment analysis of DEIRGs; (C) signaling pathways related to IL6R expression determined by GSEA.
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