Prognostic value of immune related genes in lung adenocarcinoma
- Authors:
- Published online on: September 18, 2020 https://doi.org/10.3892/ol.2020.12122
- Article Number: 259
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Copyright: © Wang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
Abstract
Introduction
In terms of incidence and mortality rate, lung cancer ranks first among all types of cancer globally, with <20% of patients surviving <5 years after diagnosis, in 2017 (1). There are two forms of lung cancer: Non-small cell lung cancer (NSCLC) and small cell lung cancer (2). NSCLC is further subdivided into lung adenocarcinoma (LUAD), squamous cell carcinoma and large cell carcinoma (3). Adenocarcinoma accounts for the largest proportion of cases, and its incidence has been increasing over the last 10 years, worldwide (4).
The primary treatments available for patients with lung cancer include surgery, chemo- and radiotherapy, molecular targeted therapy and immunotherapy. In the past few decades, researchers have improved our understanding of the role of the immune system in cancer development, and thus, immunotherapy has improved the field of tumor treatment. Of late, checkpoint inhibitors have been developed for the treatment of lung cancer (5,6); blockade of immune checkpoint proteins, including programmed death-1 (PD-1)/programmed death-ligand1 (PD-L1) and cytotoxic T-lymphocyte-associated protein 4, has shown promise in the treatment of several types of cancer, reducing tumor burden and prolonging the survival time of patients (7).
By comprehensively exploring the prognostic value of immune-related genes (IRGS), a recent study assessed individualized immune characteristics to improve the prognoses of patients with NSCLC (8). Previous studies have reported that tumor-infiltrating B cells are closely associated with a more favorable prognosis in NSCLC, cervical cancer and breast cancer (9–11). Nielsen et al (11) reported that CD20+ tumor-infiltrating lymphocytes (TILs) colocalized with activated CD8+ TILs expressed markers of antigen presentation. The group proposed that the association between CD20+ TILs and patient survival may reflect a supportive role in cytolytic immune responses.
By investigating survival associated immune-related genes, the present study aimed to elucidate the underlying molecular mechanisms of immune genes in LUAD, with a view to establish therapeutic targets and provide a basis for personalized treatment.
Materials and methods
Patients
In total, 10 pairs of LUAD and adjacent normal tissues were obtained from patients with LUAD (4 men and 6 women; median age, 55 years; age range, 33–69 years), undergoing surgery at the Jining Cancer Hospital (Jining, China) from November 2018 to March 2019. None of the patients had received chemo- or radiotherapy prior to surgery. The present study was approved by the Medical Ethics Committees of Jining Cancer Hospital, and written informed consent was provided by all patients prior to surgery. A total of 497 patients were assessed from The Cancer Genome Atlas (TCGA) database (cancer.gov/tcga), including 229 men and 268 women; median age, 66 years; age range, 33–88 years.
Data acquisition and processing
The LUAD dataset (12) containing transcriptome RNA-sequencing and clinical data of patients with LUAD was downloaded from TCGA database. A total of 497 LUAD tissues and 54 normal lung tissues were included in the present study. The list of IRGs was downloaded from the Immunology Database and Analysis Portal (ImmPort) database (13). The inclusion criteria were as follows: Patients with histologically or cytologically confirmed lung adenocarcinoma and patients with complete clinical information. The exclusion criteria were as follows: Patients with histologically or cytologically confirmed cancer other than lung adenocarcinoma and patients with OS time <10 days.
Identification of differentially expressed genes (DEGs), differentially expressed immune-related genes (DEIRGs) and survival-associated immune related genes (IRGs)
DEGs were identified using the edgeR package (version 3.53) in Rand further analyzed. A |log2 fold change| >2.0 and false discovery rate adjusted to P<0.01 were set as the thresholds (14). In addition, volcano and heat maps of the DEGs were constructed using the gplots and heat map components of the edgeR package, respectively. DEIRGs were obtained by comparison with the immune gene lists. Survival-associated IRGs were selected using univariate Cox regression analysis, which was performed using the survival package in R.
Functional enrichment analysis
To understand the underlying biological mechanisms of the IRGs, Gene Ontology (GO) annotation and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway analyses were performed using The Database for Annotation, Visualization and Integrated Discovery (david.ncifcrf.gov/) online tool (15) and cluster profiler, an R package for functional classification and enrichment of gene clusters using the hypergeometric distribution (16,17). The results of the GO and KEGG analyses were displayed using the GOplot package in R, and analyses were based on a threshold of P<0.01.
Development of the immune-related gene prognostic model (IRGPM)
Overall survival time was measured from the date of diagnosis to mortality or the last clinical evaluation. Survival-associated IRGs were selected via univariate Cox regression analysis using the R survival package. Using multivariate Cox regression analysis via the Akaike Information Criterion (18), patients with LUAD were then divided into high-risk and low-risk groups according to the median risks core value. The risk score was calculated using the following formula:
Survival Risk Score(SRS)=∑i=1k(Ci×Vi)Where k represents the number of mRNAs, Ci represents the coefficient of mRNA in multivariate Cox regression analysis and Vi represents the mRNA expression level. Kaplan-Meier plots were used to divide patients into high and low risk score groups, according to OS time.
Relationship between IRGPM and immune cell infiltration
The Tumor Immune Estimation Resource (TIMER) online database analyzes and creates a visualization of tumor infiltrating immune cells (19). TIMER reanalyzes gene expression data, which includes 10,897 samples across 32 cancer types from TCGA, to estimate the abundance of six subtypes of tumor-infiltrating immune cells, including CD4 T cells, CD8 T cells, B cells, macrophages, dendritic cells (DCs) and neutrophils. Thus, TIMER can easily be used to determine the relationship between immune cell infiltration and other parameters. Data regarding immune infiltration levels among patients with LUAD were obtained, and the association between IRGPM and immune cell infiltration was assessed.
Reverse transcription-quantitative (RT-q) PCR
Total RNA was obtained from the LUAD and corresponding adjacent normal tissues of 10 patients using TRIzol® reagent (Invitrogen; Thermo Fisher Scientific, Inc.) and then reverse transcribed into cDNA using the First Strand cDNA Synthesis kit (New England Biolabs, Inc.), according to the manufacturer's protocol. PCR amplification was performed with a SYBR Green PCR kit (ABM, Inc.), according to the manufacturer's protocol, using the Applied Biosystems 7500Real-Time PCR system (Applied Biosystems; Thermo Fisher Scientific, Inc.). The primer sequences used for qPCR are presented in Table I. The following thermocycling conditions were used for qPCR: Initial denaturation of 95°C for 10 min; 40 cycles of 95°C for 30 sec, 60°C for 30 sec and 72°C for 30 sec; and a final extension at 75°C for 7 min. Relative mRNA expression levels were measured using the 2−ΔΔCq method (20) and normalized to the internal reference gene GAPDH. All experiments were performed in triplicate.
Statistical analysis
Survival analysis of data from patients in the prognostic model was performed using the R survival package. Survival curves were generated using the Kaplan-Meier method and a log-rank test was used to compare the differences between the two groups. To validate the performance of the prognostic signature, the area under the survival receiver operating characteristic (ROC) curve was calculated using the R survival ROC package (21). The expression levels of genes between different groups were evaluated using the unpaired Student's t test. P<0.05 was considered to indicate a statistically significant difference.
Results
Identification of DEGs
Using the edgeR package, 2,672 DEGs were identified in patients with LUAD, 2,191 and 481 of which were upregulated and downregulated, respectively (Fig. 1A and B). Upon further comparison with immune gene lists from the ImmPort database, 273 DEIRGs were identified, 210 and 63 of which were up-and downregulated, respectively (Fig. 1C and D).
Construction of the prognostic model
The median gene expression was set as the cut-off value to divide all genes into two groups, high expression group and low expression group. Univariate analysis was used to identify survival-associated IRGS. The results demonstrated that high expression levels of: S100P [hazard ratio (HR), 1.218; 95% confidence interval (CI), 1.578–2.018; P=0.005), CPABP1 (HR, 1.343; 95% CI, 1.659–2.106; P=0.005), BIRC5 (HR, 1.645; 95% CI, 1.388–1.951; P=0.002), IGKV4-1 (HR, 1.665; 95% CI, 1.322–2.098; P=0.009), IL11 (HR, 1.728; 95% CI, 1.349–2.636; P<0.001), INHA (HR, 1.226; 95% CI, 0.972–2.265; P=0.004), INSL4 (HR, 1.978; 95% CI, 1.493–2.872; P=0.007) and LGR4 (HR, 1.678; 95% CI, 1.433–2.172; P=0.001) were associated with worse OS compared with the low expression group. Conversely, low expression levels of: ADRB2 (HR, 0.711; 95% CI, 0.553–0.712; P=0.004) and VIPR1 (HR, 0.651; 95% CI, 0.413–0.732; P<0.001) were associated with worse OS compared with the high expression group (Table II). Based on multivariate Cox regression analysis of survival-associated IRGs, a prognostic model was constructed which divided the patients into two groups (high risk score group and low risk score), according to OS time and the median risk score, using the following formula: (Expression levels of CRABP1*0.00326) + (expression levels of IGKV4-1*-0.00036) + (expression levels of IL-11*0.14555) + (expression levels of INHA*0.00475) + (expression levels of LGR4*0.01757) + (expression levels of VIPR1*-0.17506). The results demonstrated that the expression levels of IGKV4-1 and VIPR1 in high risk score group were significantly higher than low risk score group, while the expression levels of CRABP1, IL11, INHA and LGR4 in high risk score group were significantly lower than low risk score group (Fig. 2A). The risk coefficient (Fig. 2B) and mortality (Fig. 2C) were significantly higher in high risk score group compared with the low risk score group, respectively.
 | Table II.Univariate Cox regression analysis of immune related genes of patients with lung adenocarcinoma. |
Gene functional enrichment analysis of differentially expressed IRGs
The biological functions of 273 IRGs were further investigated using GO and KEGG analyses. The results showed that the ‘extracellular region part’ was the most frequent GO biological process category (P<0.05; Fig. 3A). The top 10 enriched GO networks and top 40 genes involved in GO networks are presented in Fig. 3A and B, respectively.
The top significantly enriched pathways were obtained using KEGG pathway analysis (Fig. 4A); these were ‘cytokine-cytokine receptor interaction’, ‘neuroactive ligand-receptor interaction’, ‘JAK-STAT signaling pathway’, ‘IL-17 signaling pathway’ and ‘viral protein interaction with cytokine and cytokine receptor’. Based on the relationship between IRGs and the top 5 KEGG pathways, a visual network was constructed using Cytoscape version 3.6.1 (Fig. 4B).
Clinical outcome of patients with LUAD using the prognostic model
Kaplan-Meier plots were used to divide patients into high and low risk score groups according to OS time. The area under the ROC curve was 0.800, suggesting that a prognostic model based on IRGs could be used to monitoring survival (Fig. 5A and B). Univariate analyses showed that high American Joint Committee on Cancer (AJCC) stage (22) (HR, 1.645; 95% CI, 1.388–1.951; P<0.001), high tumor stage (22) (HR, 1.665; 95%; CI, 1.322–2.098; P<0.001), high node stage (22) (HR, 1.928; 95% CI, 1.549–2.426; P<0.001) and high risk score (HR, 1.978; 95% CI, 1.493–2.872; P<0.001) were significant risk factors for a poor prognosis (Table III). Using multivariate analysis, a high risks core (HR, 2.071; 95% CI, 1.313–3.425; P<0.001) was found to be independently associated with a less favorable OS time (Table III). Collectively, these data indicate that the risk scores are significantly higher among patients with advanced T (Fig. 5C) and high AJCC stages (Fig. 5D).
| Table III.Univariate and Multivariate Cox regression analysis of prognostic model (risk score) and clinical features of patients with lung adenocarcinoma. |
Correlation analysis of the prognostic model and immune cell infiltration
Among the six immune cell types investigated (B cells, CD4 T cells, CD8 T cells, DCs, macrophages and neutrophils), the risk factors identified in the prognostic model were negatively correlated with B cell infiltration (r=−0.158; P=0.001; Fig. 6A); however, risk score was not associated with CD4+ T cells (r=−0.078; P=0.112; Fig. 6B), CD8+ T cells (r=−0.015; P=0.756; Fig. 6C), dendritic cells (r=−0.080; P=0.102; Fig. 6D), macrophages (r=−0.068; P=0.164; Fig. 6E) or neutrophils (r=0.018; P=0.715; Fig. 6F).
Analysis and validation of gene expression
To further validate the expression of relevant key genes in the prognostic model, three mRNAs (IL11, CARBP1 and LGR4) were randomly selected and their expression levels were evaluated in 10 pairs of LUAD and adjacent normal tissues. The expression levels of IL11, CRABP1 and LGR4 were higher in tumor tissues compared with adjacent normal tissues (Fig. 7A-C), which was consistent with the findings observed in TCGA database.
Discussion
The incidence and mortality rates of lung cancer in China are still increasing (23). A previous study indicated that IRGs are promising prognostic indicators of early stage lung cancer (8). A particular study screened for 40 genes and classified patients into high-risk and low-risk groups according to the immune signature; Patients with early non-squamous lung cancer demonstrated independent prognostic factors (8). As is well known, the treatment of advanced stage unresectable or metastatic lung cancer in China is difficult (24). Immunotherapy, such as immune checkpoint inhibitors, is primarily used for patients with metastatic lung cancer (5,6); therefore, the present study aimed to predict the prognoses of patients with LUAD using IRGs.
A total of six IRGs associated with prognosis were identified in patients with LUAD using TCGA database, and a prognostic model was established based on these genes (CRABP1, IGKV4-1, IL11, INHA, LGR4 and VIPR1). In this model, the overall survival duration of patients with high-risk disease was significantly shorter compared with patients with low-risk disease.
CRABP1 is a member of the fatty acid binding family of proteins, which binds to retinoic acid with high affinity (25). There are few studies on CRABP1 and lung cancer and the underlying molecular mechanisms of CRABP1 function in lung cancer remain unclear. Favorskaya et al demonstrated thatCRABP1 significantly alters the expression levels of CRABP in NSCLC samples (26). IGKV4-1 is inherently autoreactive and has been implicated in B-cell mediated autoimmune diseases and dysregulated B-cell tolerance (27–29). However, the function of IGKV4-1 in lung cancer remains unknown. VIPR1 is a G protein-coupled receptor that is widely distributed in the normal tissues of humans, and that serves a role in physiological functions (30). Downregulation and deletion of VIPR1 have been detected in patients with LUAD (31). Gong et al (32) demonstrated that LGR4 was expressed in LUAD tissues but not in normal lung tissue. The group reported that LGR4 and IQGAP1 served a role in the regulation of tumor growth and metastasis in lung cancer cells. IL-11 is a member of the IL-6 group and binds to its corresponding receptors. IL-11 is an important inflammatory mediator that can affect the activity of a variety of immune cells (33–35). Increased IL-11 expression levels have been associated with various types of cancer, including LUAD (36–38).
To further explain some of these potential mechanisms, gene functional enrichment analysis was performed. It was demonstrated that IRGs were primarily enriched in ‘cytokine-cytokine receptor interaction’, ‘neuroactive ligand-receptor interaction’ and the ‘JAK-STAT signaling pathway’. Among the above prognosis-related immune genes, IL-11 was associated with ‘cytokine-cytokine receptor interaction’ and the ‘JAK-STAT signaling pathway’.
Cytokines are secreted glycoproteins that function as intercellular mediators, promoting cellular proliferation, differentiation and apoptosis (39). On the other hand, cytokines secreted by tumors can promote the recruitment of immunosuppressive cells, resulting in tumor metastasis (40). Previous studies have identified a variety of cytokines that can regulate hematopoiesis, induce inflammatory responses and control immune responses through the Janus kinase (JAK) signaling pathway (41,42). The JAK family contains four members: JAK1, JAK2, JAK3 and TYK2 (43). JAK kinases are a potential target for the treatment of tumors due to the oncogenic effects and the promotion of tumor inflammatory responses via JAK signaling (41). When cytokines bind to their cognate receptors, JAK is activated and phosphorylates downstream signaling and transcriptional activator (STAT), ultimately leading to tumor invasion, angiogenesis, apoptosis and metastasis (41). IL-11 activates downstream JAK/STAT signaling proteins via a gp130 homodimer (42). The suppressor of cytokine signaling proteins regulate JAK/STAT signaling pathways by serving as feedback inhibitors of activated JAK (44). Currently, few studies have investigated IL-11 and JAK signaling pathways in tumors, and the underlying molecular mechanisms of action remain unknown. In the present study, KEGG analysis revealed that IRGs are mainly enriched in these two signaling pathways. Further network construction revealed that IL-11 is closely associated with these two pathways. The explanation of this relationship between the two pathways in the present study may provide a basis for determining the prognosis of lung cancer.
In the present study, the immune gene-related prognostic index was not only associated with the prognosis of LUAD but was also negatively correlated with immune B cell infiltration. Tumor-infiltrating B lymphocytes have seemingly conflicting effects in tumors. On the one hand, B cells function in the inhibition of tumor cell proliferation via antigen restricted tumoricidal responses; on the other hand, B cells also act by suppressing the immune system, thus promoting tumor growth, proliferation and metastasis (45). Tumor-infiltrating B lymphocyte-derived lymphotoxin has been reported to promote the progression of androgen-independent prostate cancer by activating the Nuclear Factor κ-B and STAT3 signaling pathways (46). Previous studies have shown that tumor-infiltrating CD20+ B cells reside in close proximity to CD8+ T cells, and in patients with ovarian cancer, infiltration of CD20+ B and CD8+ T cells prolongs DSS (disease-specific survival) compared with CD8+ T cell infiltration alone (11). Pinto et al (47) demonstrated that patients with LUAD, with mutated K-RAS had associated B cell infiltration. B cells also exert a number of anti-tumor effects. First, they can stimulate other immune cells to produce cytokines, particularly those that enhance the activity of CTL (cytotoxic T-lymphocytes) (48). Secondly, B cells secrete granzyme B to directly kill tumor cells (48). Furthermore, B cells can suppress pancreatic cancer via antibody-dependent mechanisms (48,49). However, the functions of a number of prognosis-related genes in lung cancer remain unclear. For example, the IGKV4-1 gene encodes a B cell receptor (50). Previous studies have not described the relationship between IGKV4-1 and lung cancer. It is unclear whether the IGKV4-1 gene serves a role in B cell infiltration in lung cancer, and further research is required to investigate the possible underlying molecular mechanisms. Due to the negative correlation between the prognostic model and B cell infiltration in the present study, some patients may have had low risk scores due to the anti-tumor effects exerted by infiltrating B lymphocytes.
The present study was not without limitations. The primary limitation was the small sample size, which will be increased in future studies. Although the conclusions of the present study were drawn based on evidence from TCGA database, only gene expression was verified. Thus, it remains critical to further verify the applicability of survival models.
In summary, the present study identified prognosis-related immune genes using TCGA database and established a prognostic model for patients with LUAD. Using multivariate analysis with other clinicopathological features, such as age, gender and TNM stage, risk score was revealed to be an independent prognostic factor, hence, the present model can predict the prognoses of patients with LUAD. In addition, the prognostic model was associated with B cell infiltration and the present study may provide novel evidence for the prognosis and immunotherapy of patients with LUAD in the future.
Acknowledgements
The authors would like to thank Dr Wei Shan (Department of Gastrointestinal Surgery, Renmin Hospital of Wuhan University) for his assistance regarding statistics.
Funding
The present study was supported by The Science and Education for Health Foundation of Suzhou for Youth (grant nos. kjxw2018030 and kjxw2018032), The Science and Technology Project Foundation of Suzhou (grant no. SS201651), The Education Research Project Foundation of Nanjing Medical University (grant no. FZS-ZD-201701), The Jiangsu Province Medical Key Discipline (grant no. ZDXKC2016007) and Suzhou Oncology Clinical Center (grant no. Szzx201506).
Availability of data and materials
The datasets generated and analyzed during the current study are available in The Cancer Genome Atlas repository (https://portal.gdc.cancer.gov/).
Authors' contributions
ZLD and WJW conceived and designed the study. YQH and JPS performed the statistical analysis. HW, MSW and YW were involved in the writing of the manuscript and in the interpretation of the results. All authors read and approved the final manuscript.
Ethics approval and consent to participate
The present study was approved by The Medical Ethics Committees of Jining Cancer Hospital (approval no. 20190067). Written informed consent was provided by all patients prior to the study start.
Patient consent for publication
Not applicable.
Competing interests
The authors declare that they have no competing interests.
Glossary
Abbreviations
Abbreviations:
|
AJCC |
American Joint Committee on Cancer |
|
CI |
confidence interval |
|
DCs |
dendritic cells |
|
DEIRGs |
differentially expressed immune-related genes |
|
GO |
gene ontology |
|
HR |
hazard ratio |
|
IRGPM |
immune-related gene prognostic model |
|
IRGs |
immune-related genes |
|
JAK-STAT |
Janus kinase-signaling and transcriptional activator |
|
KEGG |
Kyoto Encyclopedia of Genes and Genomes |
|
LUAD |
lung adenocarcinoma |
|
NSCLC |
non-small cell lung cancer |
|
OS |
overall survival |
|
PD-1 |
programmed death-1 |
|
PD-L1 |
programmed death-ligand 1 |
|
ROC |
receiver operating characteristic |
|
TCGA |
The Cancer Genome Atlas |
|
TILs |
tumor-infiltrating lymphocytes |
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