The expression of tumor necrosis factor receptor 2 is correlated with the prognosis of cancer: a systematic review and meta-analysis
Highlight box
Key findings
• High expression of tumor necrosis factor receptor 2 (TNFR2) was related to poor prognosis.
What is known and what is new?
• High expression of TNFR2 was related to poor survival.
• High expression of TNFR2 was significantly correlated with poor overall survival and disease-free survival.
What is the implication, and what should change now?
• High expression of TNFR2 was also significantly associated with higher tumor grade, higher tumor stage, and higher clinical stage.
Introduction
The most immediate task after a diagnosis of cancer is to determine the prognosis and treatment for the patients (1). The decision of prognosis is made in consideration of various clinicopathological and prognostic factors (1). With the recent development of technology, the discovery of biomarkers that can determine the prognosis of cancer is active (2).
Tumor necrosis factor receptor 2 (TNFR2) is a component of the tumor necrosis factor receptors and is involved in diverse signal pathways on the interaction with tumor necrosis factor (3,4). The signaling process of the TNFR2 pathway is not well understood (4). TNFR2 is expressed myeloid-derived suppressor cells, endothelial cells, T lymphocytes, myocardial cells, oligodendrocytes, and thymocytes (4). TNFR2 is known to play an important role in inflammatory process and immune regulation (4). Moreover, the role of TNFR2 in cancer progression has recently come to reveal (5). TNFR2 promotes the progression of cancer by upregulating the proliferation of cancer cell and inducing immune suppression and escape (4). Furthermore, reports that TNFR2 expression is related to poor prognosis are being released in various cancers, including lung, breast, esophageal, colorectal cancer, and lymphoma (3,4,6-12). However, there is no systematic review of the correlation between TNFR2 expression and the prognosis of patients with cancer.
Thus, we conducted a systematic review and meta-analysis to explore the prognostic and clinicopathological values of TNFR2 expression in patients with cancer. We present this article in accordance with the PRISMA reporting checklist (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-275/rc).
Methods
Search strategy
PubMed, Embase, and Cochrane Library were searched. The search was performed until July 2023 using the following keywords: (TNFR2 or tumor necrosis factor receptor 2) and (cancer or carcinoma or malignancy) and (prognosis or survival or outcome). A manual search was also carried out.
Inclusion and exclusion criteria
Inclusion criteria were as follows: (I) the correlation of TNFR2 expression with prognosis was presented in human cancer; (II) survival data were provided for calculating hazard ratio (HR) and 95% confidence interval (CI). The article presented with conference abstracts, review, inaccurate data, and non-English articles were excluded.
Data extraction and quality assessment
Two authors reviewed the included studies and collected basic information independently. When there was a difference in the information collected, an agreement was reached through discussion.
Two authors also assessed the quality of the enrolled studies using the Newcastle-Ottawa Scale individually. If there were any differences in the results, a consensus was reached.
Statistical analysis
A meta-analysis using StataSE12 (Stata, College Station, TX, USA) was performed. I2 statics was applied to determine the degree of heterogeneity among the enrolled studies. The pooled HR and odds ratio (OR) with 95% CI were calculated for assessing the prognostic and clinicopathological values of TNFR2 expression. We also performed funnel and filled plots with Egger test to reveal the publication bias. And the sensitivity analysis was performed to check the effect of individual studies. It was judged to be statistically significant only when the P value was less than 0.05.
Results
Basic information of the included studies
Nine eligible studies were selected through the literature search and review (Figure 1). The basic information of included studies is given in Table 1. The enrolled studies were comprised of 2,229 patients with cancer, including non-small cell lung cancer (n=2), esophageal squamous cell carcinoma (n=2), breast cancer (n=1), colorectal cancer (n=1), and lymphoma (n=3).
Table 1
| Study | Country | Cancer type | Sample size | Sex (male/female) | Age (years) | Study period | Follow-up (months) | Clinical outcome | TNFR2 detection | Cut-off value of TNFR2 expression | Survival analysis | NOS |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| Zhang et al., 2019, (4) | China | Non-small cell lung cancer | 71 | 41/30 | NA | 2006–2010 | NA | OS, DFS | Tissue (IHC) | ≥ score 4 (the product of the proportion and intensity scores) | MVA | 7 |
| Liu et al., 2018, (11) | China | Esophageal squamous cell carcinoma | 589 | 455/134 | NA | 2008–2014 | NA | OS | Tissue (IHC) | > score 4 (the product of the proportion and intensity scores) | SC | 6 |
| Yang et al., 2018, (6) | China | Esophageal squamous cell carcinoma | 431 | 245/186 | NA | 2008–2014 | December 2016 | OS | Tissue (IHC) | > score 4 (the product of the proportion and intensity scores) | SC | 7 |
| Yang et al., 2017, (3) | China | Breast cancer (ductal invasive, others) | 125 | – | NA | 2005–2010 | December 2015 | OS, DFS | Tissue (IHC) | ≥ score 4 (the product of the proportion and intensity scores) | MVA | 8 |
| Babic et al., 2016, (7) | USA | Colorectal cancer | 544 | 225/319 | NA | 1990–2010 | Median 138 (range, 46.8–246) | OS, CSS | Serum | 3,186–9,572 pg/mL | MVA | 9 |
| Nakamura et al., 2013, (12) | Japan | Diffuse large B-cell lymphoma | 154 | 87/67 | NA | 2002–2008 | NA | OS, PFS | Serum | ≥20 ng/mL | MVA | 7 |
| Heemann et al., 2012, (10) | Sweden | T-cell non-Hodgkin lymphoma | 117 | 69/48 | Median 58 (range, 18–78) | 1993–2007 | NA | OS, EFS | Serum | ≥2.16 ng/mL | MVA | 7 |
| Gregorc et al., 2007, (9) | Italy | Non-small cell lung cancer | 88 | NA | Mean 62.5 (range, 21–80) | NA | Median 44.3 | OS | Serum | >1 ng/mL | MVA | 8 |
| Goto et al., 2006, (8) | Japan | Non-Hodgkin lymphoma | 110 | 68/42 | NA | 1997–2002 | November 2003 | OS, EFS | Serum | >15 ng/mL | MVA | 8 |
TNFR2, tissue necrosis factor receptor 2; NOS, Newcastle-Ottawa Scale; NA, not available; OS, overall survival; DFS, disease-free survival; IHC, immunohistochemistry; MVA, multivariate analysis; SC, survival curve; CSS, cancer-specific survival; PFS, progression-free survival; EFS, event-free survival.
Correlation between TNFR2 expression and overall survival (OS)
The pooled HR was calculated using random effects model (I2=57.8%; P=0.02). The pooled HR for nine studies was 1.76 (95% CI: 1.37–2.27; P<0.001), indicating that high expression of TNFR2 was correlated with poor OS in patients with cancer (Figure 2A). We also performed subgroup analyses according to cancer type (solid cancer vs. lymphoma) and TNFR2 detected sample (tissue vs. serum). The analyses revealed that all groups maintained significant results (HR, 1.50; 95% CI: 1.21–1.87; P<0.001 for solid cancer; HR, 2.95; 95% CI: 1.85–4.69; P<0.001 for lymphoma; HR, 1.72; 95% CI: 1.41–2.11; P<0.001 for tissue; HR, 1.88; 95% CI: 1.19–2.98; P=0.007 for serum) (Table 2, Figure 2B,2C).
Table 2
| Subgroup | Number of studies | Number of patients | Pooled HR (95% CI) | P value | Heterogeneity | |
|---|---|---|---|---|---|---|
| I2 (%) | P value | |||||
| Cancer type | ||||||
| Solid cancer | 6 | 1,848 | 1.50 (1.21–1.87) | <0.001 | 45.1 | 0.11 |
| Lymphoma | 3 | 381 | 2.95 (1.85–4.69) | <0.001 | 0.0 | 0.45 |
| TNFR2 detected sample | ||||||
| Tissue | 4 | 1,216 | 1.72 (1.41–2.11) | <0.001 | 0.0 | 0.73 |
| Serum | 5 | 1,013 | 1.88 (1.19–2.98) | 0.007 | 73.9 | 0.004 |
TNFR2, tissue necrosis factor receptor 2; OS, overall survival; HR, hazard ratio; CI, confidence interval.
Correlation between TNFR2 expression and disease-free survival (DFS)
The pooled HR was calculated using fixed effects model (I2=0.0%; P=0.86). The pooled HR for five studies was 2.75 (95% CI: 1.92–3.92; P<0.001), implying that high expression of TNFR2 was correlated with poor DFS in patients with cancer (Figure 3A). Progression-free survival and event-free survival were considered as DFS in this analysis. There were only five studies reporting the correlation between DFS and TNFR2, so five studies were analyzed. In subgroup analyses according to cancer type (solid cancer vs. lymphoma) and TNFR2 detected sample (tissue vs. serum), all groups showed significant results (HR, 3.43; 95% CI: 1.77–6.64; P<0.001 for solid cancer and tissue; HR, 2.51; 95% CI: 1.64–3.83; P<0.001 for lymphoma and serum) (Table 3, Figure 3B,3C).
Table 3
| Subgroup | Number of studies | Number of patients | Pooled HR (95% CI) | P value | Heterogeneity | |
|---|---|---|---|---|---|---|
| I2 (%) | P value | |||||
| Cancer type | ||||||
| Solid cancer | 2 | 196 | 3.43 (1.77–6.64) | <0.001 | 0.0 | 0.43 |
| Lymphoma | 3 | 381 | 2.51 (1.64–3.83) | <0.001 | 0.0 | 0.97 |
| TNFR2 detected sample | ||||||
| Tissue | 2 | 196 | 3.43 (1.77–6.64) | <0.001 | 0.0 | 0.43 |
| Serum | 3 | 381 | 2.51 (1.64–3.83) | <0.001 | 0.0 | 0.97 |
TNFR2, tissue necrosis factor receptor 2; DFS, disease-free survival; HR, hazard ratio; CI, confidence interval.
Correlation between TNFR2 expression and clinicopathological factors in solid cancer
High expression of TNFR2 was significantly correlated with higher tumor grade (OR, 1.58; 95% CI: 1.26–1.98; P<0.001), higher tumor stage (OR, 2.41; 95% CI: 1.62–3.60; P<0.001) and higher clinical stage (OR, 1.80; 95% CI: 1.44–2.23; P<0.001), but not with age, gender, tumor size and lymph node metastasis (Table 4, Figure 4A-4C).
Table 4
| Factors | Number of studies | Number of patients | Pooled OR (95% CI) | P value | Heterogeneity | ||
|---|---|---|---|---|---|---|---|
| I2 (%) | P value | Model | |||||
| Age (old vs. young) | 4 | 1,216 | 1.07 (0.85–1.35) | 0.57 | 0.0 | 0.81 | Fixed |
| Sex (male vs. female) | 4 | 1,635 | 1.05 (0.84–1.30) | 0.68 | 0.0 | 0.84 | Fixed |
| Tumor size (large vs. small) | 3 | 785 | 1.30 (0.38–4.39) | 0.68 | 76.0 | 0.02 | Random |
| Tumor grade (high vs. low) | 4 | 1,689 | 1.58 (1.26–1.98) | <0.001 | 48.5 | 0.12 | Fixed |
| Tumor stage (high vs. low) | 2 | 556 | 2.41 (1.62–3.60) | <0.001 | 30.0 | 0.23 | Fixed |
| Lymph node metastasis (present vs. absent) | 4 | 1,216 | 1.14 (0.74–1.76) | 0.55 | 63.2 | 0.043 | Random |
| Clinical stage (high vs. low) | 5 | 1,760 | 1.80 (1.44–2.23) | <0.001 | 16.7 | 0.31 | Fixed |
TNFR2, tissue necrosis factor receptor 2; OR, odds ratio; CI, confidence interval.
Publication bias
The funnel plot for OS looked asymmetrical. Indeed, Egger test proved a small-study effect (P=0.02). However, the pooled HR was still significant in the filled funnel plot (HR, 1.47; 95% CI: 1.13–1.91; P=0.004) (Figure 5A,5B).
The funnel plot for DFS did not show publication bias (Egger test; P=0.19). The filled test revealed that initial data was unchanged (HR, 2.75; 95% CI: 1.92–3.92; P<0.001) (Figure 5C,5D).
Sensitivity analysis
The sensitivity analyses demonstrated that the initial results were reliable and consistent even excluding the effects of individual studies (HR, 1.54; 95% CI: 1.34–1.77 for OS; HR, 2.75; 95% CI: 1.92–3.92 for DFS) (Figure 6A,6B).
Discussion
TNFR2 is a transmembrane protein consisting of an extracellular domain with four complementarity determining regions (5). TNFR2 is known to play distinct roles in cancer progression and metastasis (5). Some researchers have reported that TNFR2 participates in enhancing TNF-induced or vascular endothelial growth factor-related cancer cell proliferation and TNFR2 promotes cancer progression and metastasis by inducing an immunosuppressive microenvironment (5).
More recently, the prognostic role of TNFR2 expression in cancer has been revealed. Considering the results of the studies in cancer tissue, Liu et al. and Yang et al. demonstrated that high expression of TNFR2 is correlated with poor OS in patients with esophageal squamous cell carcinoma (6,11). Zhang et al. demonstrated that high expression of TNFR2 is correlated with shorter OS and DFS in patients with non-small cell lung cancer (4). Yang et al. reported that TNFR2 expression is shown to significantly impact the DFS of patients with breast cancer (3). With respect to serum, Babic et al. revealed that higher TNFR2 levels are correlated with a significant increase in overall mortality of patients with colorectal cancer (7). Nakamura et al., Heemann et al., and Goto et al. showed that high level of serum TNFR2 is related to disease progression and shorter OS in patients with lymphoma (8,10,12).
Here, a meta-analysis was conducted for a systematic understanding of the correlation between TNFR2 expression and survival in patients with cancer.
In this study, we demonstrated that high expression of TNFR2 was correlated with poor OS and DFS in patients with cancer. In addition, we revealed that the significant association was maintained regardless of cancer type (solid cancer vs. lymphoma) and TNFR2 detected sample (tissue vs. serum). We also identified that high expression of TNFR2 was significantly correlated with higher tumor grade, tumor stage, and clinical stage in solid cancer.
For the first time, we systematically examined the correlation between TNFR2 expression and the prognosis in patients with cancer. However, this study has some limitations. Firstly, the number of included studies and sample size were limited. Secondly, several HR was calculated from the survival curve, which might cause a slight error. Lastly, the articles studied through serum might have influenced our results because the cut-off value of TNFR2 expression varies.
Conclusions
In summary, high expression of TNFR2 was related to poor prognosis and could be a prognostic factor in patients with cancer.
Acknowledgments
Funding: This work was supported by
Footnote
Reporting Checklist: The authors have completed the PRISMA reporting checklist. Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-275/rc
Peer Review File: Available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-275/prf
Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://tcr.amegroups.com/article/view/10.21037/tcr-24-275/coif). The authors have no conflicts of interest to declare.
Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.
Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.
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