The Prognostic Value of Toll-Like Receptors in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis
Abstract
:1. Introduction
2. Results
2.1. Study Selection
2.2. Study Characteristics
2.3. Quality and Bias Assessment
2.4. The Cutoff Values
2.5. TLR and Clinicopathological Parameters of HNSCC Patients
2.6. TLR and the Viral Status of HNSCC Patients
2.7. TLR and the Survival Outcomes of HNSCC Patients
2.8. Meta-Analysis Results
3. Discussion
4. Materials and Methods
4.1. Protocol and Registration
4.2. Inclusion and Exclusion Criteria
4.3. Search Strategy and Study Screening
4.4. Data Extraction and Study Items
4.5. Assessment of Study Quality and Reporting Bias
4.6. Data Synthesis and Statistical Analysis
Supplementary Materials
Author Contributions
Funding
Acknowledgments
Conflicts of Interest
Abbreviations
TLR | Toll-like receptor |
HNSCC | Head and neck squamous cell carcinoma |
OPSCC | Oropharyngeal squamous cell carcinoma |
OSCC | Oral squamous cell carcinoma |
NPC | Nasopharyngeal carcinoma |
BOTSCC | Base-of-tongue squamous cell carcinoma |
OTSCC | Oral tongue squamous cell carcinoma |
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Study | Origin | Tumour Type | Tumour Stage | Cases | Age | Study Period | TLR | Compliance to REMARK |
---|---|---|---|---|---|---|---|---|
[10] | Finland | OPSCC | I–IV | 143 | HPV+ 60.8 HPV− 62.2 (M) | 2012–2016 | TLR-5 | Fulfilled all items |
[12] | China | OSCC | T1–T4 | 90 | 62.5 (M) | 2005–2008 | TLR-3 | Lacked item No. 5 |
[17] | Finland | NPC | I–IV | 207 | 57 (M) | 1990–2009 | TLR-1, TLR-2, TLR-4, TLR-5, TLR-7, TLR-9 | Fulfilled all items |
[18] | Sweden | BOTSCC | I–IV | 77 | 62 (M) | 2000–2011 | TLR-5, TLR-7 | Lacked item No. 5 |
[11] | Finland | OPSCC | I–IV | 331 | - | 2000–2009 | TLR-5, TLR-7, TLR-9 | Fulfilled all items |
[13] | China | OSCC | I–IV | 110 | 60 (Med) | 2006–2010 | TLR-4 | Lacked item No. 5 |
[22] | China | TSCC | I–IV | 60 | 57 (M) | 2013–2015 | TLR-1 | Lacked items No. 1, 4, 5 |
[14] | China | OSCC | I–IV | 166 | - | 2000–2011 | TLR-7 | Lacked item No. 3 |
[19] | Finland | OTSCC | 1–4 | 197 | 65 (Med) | 1981–2009 | TLR-9 | Fulfilled all items |
[20] | Finland | OTSCC | I–IV | 73 | 59 (Med) | 1992–2002 | TLR-2, TLR-4, TLR-5, TLR-7, TLR-9 | Lacked item No. 5 |
[15] | China | OSCC | T1–T4 | 61 | 59.31 (M) | 1992–2007 | TLR-4 | Lacked items No. 4,5 |
[16] | Germany | OSCC | I–IV | 191 | - | - | TLR-5 | Lacked item No. 1 |
[21] | Finland | OTSCC | 1–4 | 119 | 66 (Med) | 1981–2009 | TLR-5 | Fulfilled all items |
Study | Antibody Info | Dilution | Tissue | Scoring Grade | Cutoff Value |
---|---|---|---|---|---|
[10] | TLR-5: (mAb, Mo), Novus | 1:100 | TMA | Neg. 0, mild 1, moderate 2, strong 3 | Values (1–3) are scored as positive |
[12] | TLR-3: Abcam; clonality: ND | 1:100 | FFPE | Low, high | - |
[17] | TLR-1: (Rb) Santa Cruz Bio. Inc. TLR-2: (pAb, Rb), Santa Cruz. TLR-4: (pAb, Rb) Santa Cruz. TLR-5: (mAb, Mo), Novus Biologicals. TLR-7: (pAb, Rb), Imgenex/Novus Biologicals. TLR-9: (pAb, Rb), Santa Cruz | TLR-1 1:100, TLR-2 1:200, TLR-4 1:300, TLR-5 1:100, TLR-7 1:300, TLR-9 1:100 | FFPE | Neg., mild, moderate, or strong | It is required that >80% of tumour cells in the sample stained positively |
[18] | TLR-5: (mAb, Mo), Imgenex TLR-7: (mAb, Rb), Imgenex | TLR-5 1:200 TLR-7 1:300 | FFPE | Neg., weak, medium, strong | - |
[11] | TLR-5: (mAb, Mo), Imgenex TLR-7: (mAb, Rb), Imgenex TLR-9: (pAb, Rb), Santa Cruz Bio. Inc. | TLR-5 1:200, TLR-7 1:300, TLR-9 1:100 | TMA | 0–3 (0 = none, 3 = strong) | Values 1–3 are scored as positive |
[13] | TLR-4: (pAb, Rb) Boster Biological Tech Co. | 1:150 | FFPE | Low, high | IRS 3 |
[22] | TLR-1: (pAb), Abcam | 1:100 | FFPE | Percentage of stained cells 0–4 | IRS: low 0–3, high 2–4. The (%) of stained cells was 0 for ≤ 25% staining; 1 for 25–50%; 2 for 50%; 3 for 51–75%; and 4 for more than 75% staining |
[14] | TLR-7: Abcam; clonality: ND | - | FFPE | Grade 1–3 | Grade 1 (1–3) Grade 2 (4–6) Grade 3 (7–9) |
[19] | TLR-9: (mAb, Mo, IgG1), Imgenex | 1:150 | FFPE | Low, high | Histoscore: low 0–64, high 65–300 |
[20] | TLR-2: (pAb, Rb), Santa Cruz Bio. Inc. TLR-4: (pAb Rb), Santa Cruz Bio. Inc. TLR-5: (mAb), Imgenex. TLR-7: (pAb) Imgenex. TLR-9: (pAb), Santa Cruz Bio. Inc. | TLR-2 1:50, TLR-4 1:50, TLR-5 1:200, TLR-7 1:300, TLR-9 1:100 | TMA | TLR-2, 4 and 7: 0–4 (0 = none, 4 = very high), TLR-5 and 9: 0–3 (0 = neg., 3 = strongly positive) | Low: none/mild High: mod./strong |
[15] | TLR-4: Protein Tech & Affbiotect | 1:150 | FFPE | Over-expressed, under-expressed | 50% |
[16] | TLR-5: (mAb, Mo) (Imgenex) | 1:100 | FFPE | Low expression; high expression | 7% |
[21] | TLR-5: (mAb, Mo, IgG2a), Imgenex | 1:150 | FFPE | Weak and strong expression | Histoscore: weak 0–135; strong 136–300 |
Study | TLR | Endpoint | Adjusted Analysis | Adjusted Factors | Results Interpretation |
---|---|---|---|---|---|
[10] | TLR-5 | DSS | HR = 2.5, P = 0.129, 95% CI = 0.8–8.1 | Gender, age, smoking, TN-class, stage, treatment, HPV status | High TLR-5 expression was an independent indicator of poor DSS in those with HPV-positive OPSCC. High TLR-5 was significantly associated with LN-status, tumour site and grade. |
[12] | TLR-3 | OS | - | - | TLR-3 expression was associated with poor prognosis and shorter OS. Higher TLR-3 was also associated with pathologic grade. |
[17] | TLR-1 TLR-2 TLR-4 TLR-5 TLR-7 TLR-9 | OS | TLR-7: HR = 0.37, P = 0.018, 95% CI = 0.16–0.84 | Gender, age, ethnicity, smoking, TN-class, stage, histology, virus status, treatment, irradiation technique | Patients with positive TLR-7 tumour expression had better OS than those with no TLR-7 expression. |
DSS | TLR-7: HR = 0.39, P = 0.046, 95% CI = 0.15–0.98 | ||||
[18] | TLR-5 TLR-7 | DSS | - | - | TLR-5 or TLR-7 did not have a statistically significant correlation with clinical outcome or survival. |
DFS | - | ||||
[11] | TLR-5 TLR-7 TLR-9 | DSS | TLR-7: HR = 3.2, P = 0.027, 95% CI = 1.1–9.0 | Gender, smoking, TN-class, HPV status, treatment | High expression of TLR-5 and low expression of TLR-7 are correlated with poor DSS and RFS of HPV-positive patients. |
RFS | - | ||||
[13] | TLR-4 | OS | RR=2.334, P=0.006, 95% CI=1.277-4.267 | TN-stage, adjuvant therapy, differentiation, invasion depth, cytoplasmic and nuclear NF-kBp65 | High TLR-4 expression was an independent prognostic factor and significantly associated with lower DFS, DSS and OS. High TLR-4 expression was correlated with pTNM-stage, differentiation and invasion. |
DSS | RR=2.495, P=0.005, 95% CI=1.321-4.712 | ||||
DFS | RR=2.888, P=0.001, 95% CI=1.532-5.443 | ||||
[22] | TLR-1 | - | - | - | TLR-1 plays an inhibitory role in the development and progression of TSCC. High TLR-1 was correlated with TNM-staging. |
[14] | TLR-7 | OS | HR = 1.253, P = 0.547 (NS), 95% CI = 0.601–2.613 | Gender, age, smoking, TNM-stage, differentiation, LNM, inflammation | High expression of TLR-7 in tumour cells correlated with shorter OS but not with DFS. On the contrary, high TLR-7 in stromal fibroblast-like cells was correlated with better survival time. High TLR-7 was also significantly associated with tumour differentiation. |
DFS | - | ||||
[19] | TLR-9 | CSS | HR = 1.810, P = 0.024, 95% CI = 1.053–3.112 | Age, tumour stage, histologic grade | High TLR-9 expression was an independent predictor of poor CSS. TLR-9 correlates significantly with tumour grade. |
[20] | TLR-2 TLR-4 TLR-5 TLR-7 TLR-6 | OS | - | Pathologic T-stage, grade, presence of occult neck metastases, and invasion | Negative or mild TLR-5 expression was related to worse DSS. |
DSS | - | ||||
DFS | - | ||||
[15] | TLR-4 | POS | - | - | Patients with TLR-4 amplification had a shorter POS and high TLR-4 expression also correlates with T-stage, histological classification and metastasis. |
[16] | TLR-5 | DFS | - | - | TLR-5 expression was not associated with any clinicopathological characteristics or impact on survival. |
[21] | TLR-5 | DFS | HR = 3.587, 95% CI = 1.632–7.882 | Gender, age, stage, histologic grade, adjuvant therapy | Strong TLR-5 expression was independent prognostic factor associated with reduced DFS and CSS. |
CSS | - |
Study | Number of Cases | Country | TLR Type | Endpoint | Hazard Ratio (95% CI) | Relative Weight, % |
---|---|---|---|---|---|---|
All Studies | ||||||
[21] | 119 | Finland | TLR-5 | DFS | 3.59 (1.63–7.88) | 2.00 |
[10] | 143 | Finland | TLR-5 | DSS | 2.50 (0.80–8.10) | 3.09 |
[11] | 331 | Finland | TLR-7 | DSS | 3.20 (1.10–9.00) | 16.33 |
[14] | 166 | China | TLR-7 | OS | 1.25 (0.60–2.61) | 2.32 |
[17] | 207 | Finland | TLR-7 | DSS | 0.39 (0.15–0.98) | 16.75 |
[17] | 207 | Finland | TLR-7 | OS | 0.37 (0.16–0.84) | 30.51 |
[19] | 197 | Finland | TLR-9 | CSS | 1.81 (1.05–3.11) | 29.00 |
Pooled overall estimate | 0.96 (0.39–1.54) | 100.00 | ||||
Heterogeneity measures | I-squared = 61.8% (p-value = 0.0015), Tau-squared = 0.2533 | |||||
Subgroup Analysis (TLR subtype) | ||||||
Study | Number of Cases | Country | TLR Type | Endpoint | Hazard Ratio (95% CI) | Relative Weight, % |
TLR-5 Studies | ||||||
[21] | 119 | Finland | TLR-5 | DFS | 3.59 (1.63–7.88) | 57.70 |
[10] | 143 | Finland | TLR-5 | DSS | 2.50 (0.80–8.10) | 42.30 |
Pooled overall estimate | 3.13 (0.76–5.50) | 100.00 | ||||
Heterogeneity measures | I-squared = 0.0% (p-value = 0.657), Tau-squared = 0.000 | |||||
TLR-7 Studies | ||||||
[11] | 331 | Finland | TLR-7 | DSS | 3.20 (1.10–9.00) | 0.91 |
[14] | 166 | China | TLR-7 | OS | 1.25 (0.60–2.61) | 11.98 |
[17] | 207 | Finland | TLR-7 | OS | 0.37 (0.16–0.84) | 47.27 |
[17] | 207 | Finland | TLR-7 | DSS | 0.39 (0.15–0.98) | 39.84 |
Pooled overall estimate | 0.51 (0.13–0.89) | 100.00 | ||||
Heterogeneity measures | I-squared = 34.6% (p-value = 0.205), Tau-squared = 0.0489 |
Inclusion Criteria | Exclusion Criteria |
---|---|
Original research articles | The retrieved records were case reports; reviews; letters; etc. |
Histological tissue samples from human patients | Animal model studies and tests |
Patients diagnosed with HNSCC | Articles not written in English language |
Studies reported the association between TLR immunoexpression and the survival outcomes | Insufficient information of the correlation between clinical features and/or survival outcomes |
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Hasnat, S.; Hujanen, R.; Nwaru, B.I.; Salo, T.; Salem, A. The Prognostic Value of Toll-Like Receptors in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. Int. J. Mol. Sci. 2020, 21, 7255. https://doi.org/10.3390/ijms21197255
Hasnat S, Hujanen R, Nwaru BI, Salo T, Salem A. The Prognostic Value of Toll-Like Receptors in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences. 2020; 21(19):7255. https://doi.org/10.3390/ijms21197255
Chicago/Turabian StyleHasnat, Shrabon, Roosa Hujanen, Bright I. Nwaru, Tuula Salo, and Abdelhakim Salem. 2020. "The Prognostic Value of Toll-Like Receptors in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis" International Journal of Molecular Sciences 21, no. 19: 7255. https://doi.org/10.3390/ijms21197255
APA StyleHasnat, S., Hujanen, R., Nwaru, B. I., Salo, T., & Salem, A. (2020). The Prognostic Value of Toll-Like Receptors in Head and Neck Squamous Cell Carcinoma: A Systematic Review and Meta-Analysis. International Journal of Molecular Sciences, 21(19), 7255. https://doi.org/10.3390/ijms21197255