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Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Molecular Oncology".

Deadline for manuscript submissions: closed (30 November 2020) | Viewed by 65385

Special Issue Editor

Prof. Dr. Sven Perner

E-Mail Website
Guest Editor
1. Institute of Pathology, University Hospital Schleswig-Holstein, 23560 Luebeck, Germany
2. Research Center Borstel, Department of Pathology, Parkallee 3a, 23845 Borstel, Germany
Interests: prostate cancer; lung cancer; head and neck cancer; molecular biology; molecular pathology; biomarker; immunoncology

Special Issue Information

Dear Colleagues,

Squamous cell carcinoma of the head and neck region (HNSCC) is the sixth most common cancer entity world-wide. However, despite achievements in other malignancies, the therapeutic options for HNSCC have still not been properly developed. Surgery or platin-based radiochemo therapy are incriminatory and often mutilating for patients. New therapeutic approaches such as immune check point inhibitors and kinase inhibitors do not have as much of an impact on HNSCC as on other tumor entities. This Issue focuses on deciphering the molecular basis of HNSCC in order to develop new alternative therapeutic options and biomarkers for early detection and risk stratification of primary and recurrent HNSCC. New therapeutic approaches are necessary, since the two-year survival of grade III and IV tumors is still only 30%. In particular, having reliable biomarkers to assess the risk for the clinically challenging existence of occult lymph node metastasis would be an important clinical tool to decide whether surgery or irradiation of the neck is necessary. The clinical follow-up of HNSCC patients is still based on clinical examination, ultrasound, and x-ray, while there is still no established biomarker for the detection of disease recurrence.

For this Issue, we would like to invite researchers and clinicians to submit their work in order to enlighten this heavily under researched field of HNSCC. 

Prof. Dr. Sven Perner
Guest Editor

Manuscript Submission Information

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Editorial

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1 pages, 134 KiB  
Editorial
Editorial for the Special Issue “Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology”
by Sven Perner and Christian Idel
Int. J. Mol. Sci. 2021, 22(4), 1592; https://doi.org/10.3390/ijms22041592 - 05 Feb 2021
Cited by 1 | Viewed by 1478
Abstract
Squamous cell carcinoma of the head and neck (HNSCC) is the sixth most common cancer worldwide [...] Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)

Research

Jump to: Editorial, Review

15 pages, 1217 KiB  
Article
LAG-3, TIM-3 and VISTA Expression on Tumor-Infiltrating Lymphocytes in Oropharyngeal Squamous Cell Carcinoma—Potential Biomarkers for Targeted Therapy Concepts
by Nora Wuerdemann, Katharina Pütz, Hans Eckel, Rishabh Jain, Claus Wittekindt, Christian U. Huebbers, Shachi J. Sharma, Christine Langer, Stefan Gattenlöhner, Reinhard Büttner, Ernst-Jan Speel, Malte Suchan, Steffen Wagner, Alexander Quaas and Jens P. Klussmann
Int. J. Mol. Sci. 2021, 22(1), 379; https://doi.org/10.3390/ijms22010379 - 31 Dec 2020
Cited by 22 | Viewed by 4435
Abstract
Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and [...] Read more.
Tumor growth and survival requires a particularly effective immunosuppressant tumor microenvironment (TME) to escape destruction by the immune system. While immunosuppressive checkpoint markers like programmed cell death 1 ligand (PD-L1) are already being targeted in clinical practice, lymphocyte-activation-protein 3 (LAG-3), T-cell immunoglobulin and mucin-domain containing-3 (TIM-3) and V-domain Ig suppressor of T cell activation (VISTA) inhibitors are currently under investigation in clinical trials. Reliable findings on the expression status of those immune checkpoint inhibitors on tumor-infiltrating lymphocytes (TILs) in the TME of oropharyngeal squamous cell carcinoma (OPSCC) are lacking. This work aims to describe the expression of LAG-3, TIM-3, and VISTA expression in the TME of OPSCC. We created a tissue microarray of paraffin-embedded tumor tissue of 241 OPSCC. Expression of the immune checkpoint protein LAG-3, TIM-3, and VISTA in OPSCC was evaluated using immunohistochemistry and results were correlated with CD8+ T-cell inflammation and human papillomavirus (HPV)-status. 73 OPSCC stained positive for LAG-3 (31%; HPV+:44%; HPV-:26%, p = 0.006), 122 OPSCC stained positive for TIM-3 (51%; HPV+:70%; HPV-:44%, p < 0.001) and 168 OPSCC (70%; HPV+:75%; HPV-:68%, p = 0.313) for VISTA. CD8+ T-cells were significantly associated with LAG-3, TIM-3 and VISTA expression (p < 0.001, p < 0.001, p = 0.007). Immune checkpoint therapy targeting LAG-3, TIM-3, and/or VISTA could be a promising treatment strategy especially in HPV-related OPSCC. Future clinical trials investigating the efficacy of a checkpoint blockade in consideration of LAG-3, TIM-3, and VISTA expression are required. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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20 pages, 4996 KiB  
Article
Characterization and Differentiation of the Tumor Microenvironment (TME) of Orthotopic and Subcutaneously Grown Head and Neck Squamous Cell Carcinoma (HNSCC) in Immunocompetent Mice
by Matthias Brand, Simon Laban, Marie-Nicole Theodoraki, Johannes Doescher, Thomas K. Hoffmann, Patrick J. Schuler and Cornelia Brunner
Int. J. Mol. Sci. 2021, 22(1), 247; https://doi.org/10.3390/ijms22010247 - 29 Dec 2020
Cited by 13 | Viewed by 2846
Abstract
For the development and evaluation of new head and neck squamous cell carcinoma (HNSCC) therapeutics, suitable, well-characterized animal models are needed. Thus, by analyzing orthotopic versus subcutaneous models of HNSCC in immunocompetent mice, we evaluated the existence of adenosine-related immunosuppressive B- and T [...] Read more.
For the development and evaluation of new head and neck squamous cell carcinoma (HNSCC) therapeutics, suitable, well-characterized animal models are needed. Thus, by analyzing orthotopic versus subcutaneous models of HNSCC in immunocompetent mice, we evaluated the existence of adenosine-related immunosuppressive B- and T lymphocyte populations within the tumor microenvironment (TME). Applying the SCC VII model for the induction of HNSCC in immunocompetent C3H/HeN mice, the cellular TME was characterized after tumor initiation over time by flow cytometry. The TME in orthotopic grown tumors revealed a larger population of tumor-infiltrating lymphocytes (TIL) with more B cells and CD4+ T cells than the subcutaneously grown tumors. Immune cell populations in the blood and bone marrow showed a rather distinct reaction toward tumor induction and tumor location compared to the spleen, lymph nodes, or thymus. In addition, large numbers of immunosuppressive B- and T cells were identified within the TME but also in secondary lymphoid organs, independently of the tumor initiation site. The altered immunogenic TME may influence the response to any treatment attempt. Moreover, when analyzing the TME and other lymphoid organs of tumor-bearing mice, we observed conditions reflecting largely those of patients suffering from HNSCC suggesting the C3H/HeN mouse model as a suitable tool for studies aiming to target immunosuppression to improve anti-cancer therapies. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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14 pages, 1907 KiB  
Article
HGF-Induced PD-L1 Expression in Head and Neck Cancer: Preclinical and Clinical Findings
by Verena Boschert, Jonas Teusch, Anwar Aljasem, Philipp Schmucker, Nicola Klenk, Anton Straub, Max Bittrich, Axel Seher, Christian Linz, Urs D. A. Müller-Richter and Stefan Hartmann
Int. J. Mol. Sci. 2020, 21(22), 8770; https://doi.org/10.3390/ijms21228770 - 20 Nov 2020
Cited by 6 | Viewed by 2869
Abstract
Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is a widespread disease with a low survival rate and a high risk of recurrence. Nowadays, immune checkpoint inhibitor (ICI) treatment is approved for HNSCC as a first-line treatment in recurrent and metastatic disease. ICI treatment yields a clear survival benefit, but overall response rates are still unsatisfactory. As shown in different cancer models, hepatocyte growth factor/mesenchymal–epithelial transition (HGF/Met) signaling contributes to an immunosuppressive microenvironment. Therefore, we investigated the relationship between HGF and programmed cell death protein 1 (PD-L1) expression in HNSCC cell lines. The preclinical data show a robust PD-L1 induction upon HGF stimulation. Further analysis revealed that the HGF-mediated upregulation of PD-L1 is MAP kinase-dependent. We then hypothesized that serum levels of HGF and soluble programmed cell death protein 1 (sPD-L1) could be potential markers of ICI treatment failure. Thus, we determined serum levels of these proteins in 20 HNSCC patients before ICI treatment and correlated them with treatment outcomes. Importantly, the clinical data showed a positive correlation of both serum proteins (HGF and sPD-L1) in HNSCC patient’s sera. Moreover, the serum concentration of sPD-L1 was significantly higher in ICI non-responsive patients. Our findings indicate a potential role for sPD-L1 as a prognostic marker for ICI treatment in HNSCC. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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16 pages, 3072 KiB  
Article
PD-L1 Influences Cell Spreading, Migration and Invasion in Head and Neck Cancer Cells
by Jonas Eichberger, Daniela Schulz, Kristian Pscheidl, Mathias Fiedler, Torsten Eugen Reichert, Richard Josef Bauer and Tobias Ettl
Int. J. Mol. Sci. 2020, 21(21), 8089; https://doi.org/10.3390/ijms21218089 - 29 Oct 2020
Cited by 27 | Viewed by 3467
Abstract
The programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis blockade has been implemented in advanced-stage tumor therapy for various entities, including head and neck squamous cell carcinoma (HNSCC). Despite a promising tumor response in a subgroup of HNSCC patients, the majority [...] Read more.
The programmed cell death protein-1 (PD-1)/programmed cell death ligand-1 (PD-L1) axis blockade has been implemented in advanced-stage tumor therapy for various entities, including head and neck squamous cell carcinoma (HNSCC). Despite a promising tumor response in a subgroup of HNSCC patients, the majority suffer from disease progression. PD-L1 is known to influence several intrinsic mechanisms in cancer cells, such as proliferation, apoptosis, migration and invasion. Here, we modulated PD-L1 expression in three HNSCC cell lines with differential intrinsic PD-L1 expression. In addition to an alteration in the epithelial-to-mesenchymal transition (EMT) marker expression, we observed PD-L1-dependent cell spreading, migration and invasion in a spheroid spreading assay on four different coatings (poly-L-lysine, collagen type I, fibronectin and Matrigel®) and a chemotactic transwell migration/invasion assay. Furthermore, the overexpression of PD-L1 led to increased gene expression and small interfering ribonucleic acid (siRNA) knockdown and decreased gene expression of Rho-GTPases and related proteins in a RT2 Profiler™ PCR Array. Rac1 and Rho-GTPase pulldown assays revealed a change in the activation state concordantly with PD-L1 expression. In summary, our results suggest a major role for PD-L1 in favoring cell motility, including cell spreading, migration and invasion. This is presumably caused by altered N-cadherin expression and changes in the activation states of small Rho-GTPases Rho and Rac1. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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23 pages, 2374 KiB  
Article
DNA Methylome Distinguishes Head and Neck Cancer from Potentially Malignant Oral Lesions and Healthy Oral Mucosa
by Nina Milutin Gašperov, Ivan Sabol, Ksenija Božinović, Emil Dediol, Marinka Mravak-Stipetić, Danilo Licastro, Simeone Dal Monego and Magdalena Grce
Int. J. Mol. Sci. 2020, 21(18), 6853; https://doi.org/10.3390/ijms21186853 - 18 Sep 2020
Cited by 10 | Viewed by 2607
Abstract
There is a strong need to find new, good biomarkers of head and neck squamous cell carcinoma (HNSCC) because of the bad prognoses and high mortality rates. The aim of this study was to identify the potential biomarkers in HNSCC that have differences [...] Read more.
There is a strong need to find new, good biomarkers of head and neck squamous cell carcinoma (HNSCC) because of the bad prognoses and high mortality rates. The aim of this study was to identify the potential biomarkers in HNSCC that have differences in their DNA methylome and potentially premalignant oral lesions, in comparison to healthy oral mucosa. In this study, 32 oral samples were tested: nine healthy oral mucosae, 13 HNSCC, and 10 oral lesions for DNA methylation by the Infinium MethylationEPIC BeadChip. Our findings showed that a panel of genes significantly hypermethylated in their promoters or specific sites in HNSCC samples in comparison to healthy oral samples, which are mainly oncogenes, receptor, and transcription factor genes, or genes included in cell cycle, transformation, apoptosis, and autophagy. A group of hypomethylated genes in HNSCC, in comparison to healthy oral mucosa, are mainly involved in the host immune response and transcriptional regulation. The results also showed significant differences in gene methylation between HNSCC and potentially premalignant oral lesions, as well as differently methylated genes that discriminate between oral lesions and healthy mucosa. The given methylation panels point to novel potential biomarkers for early diagnostics of HNSCC, as well as potentially premalignant oral lesions. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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13 pages, 2157 KiB  
Article
Prognostic Value of the Overexpression of Fatty Acid Metabolism-Related Enzymes in Squamous Cell Carcinoma of the Head and Neck
by Ying-Wen Su, Pao-Shu Wu, Sheng-Hsiang Lin, Wen-Yu Huang, Yu-Shao Kuo and Hung-Pin Lin
Int. J. Mol. Sci. 2020, 21(18), 6851; https://doi.org/10.3390/ijms21186851 - 18 Sep 2020
Cited by 13 | Viewed by 2149
Abstract
Reprogramming of cellular energy metabolism, such as lipid metabolism, is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). However, whether protein expression related to fatty acid oxidation (FAO) affects survival in SCCHN remains unclear. We aimed to investigate FAO-related [...] Read more.
Reprogramming of cellular energy metabolism, such as lipid metabolism, is a hallmark of squamous cell carcinoma of the head and neck (SCCHN). However, whether protein expression related to fatty acid oxidation (FAO) affects survival in SCCHN remains unclear. We aimed to investigate FAO-related enzyme expression and determine its correlation with clinicopathological variables in SCCHN patients. Immunohistochemical analysis (IHC) of FAO-related protein expression, including carnitine palmitoyltransferase 1 (CPT1), the acyl-CoA dehydrogenase family, and fatty acid synthase (FAS), was performed using tissue microarrays from 102 resected SCCHN tumors. Expressions were categorized according to IHC scores, and the statistical association with clinicopathological factors was determined. Moderate-to-high expression of long-chain acyl-CoA dehydrogenase (LCAD) had a protective role against cancer-related death (adjusted hazard ratio (HR), 0.2; 95% confidence interval (CI), 0.05–0.87) after covariate adjustment. Age and clinical stage remained independent predictors of survival (adjusted HR, 1.75; 95% CI, 1.22–2.49 for age; adjusted HR, 14.33; 95% CI, 1.89–108.60 for stage III/IV disease). Overexpression of medium-chain acyl-CoA dehydrogenase and FAS correlated with advanced tumor stage (T3/T4); however, none of these factors were independent predictors of survival. Several FAO-related enzymes were upregulated and LCAD overexpression had a protective effect on overall survival in advanced SCCHN patients. FAO-related-enzyme expression might have a prognostic impact on survival outcomes in SCCHN. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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16 pages, 3346 KiB  
Article
Peripheral Cytokine Levels Differ by HPV Status and Change Treatment-Dependently in Patients with Head and Neck Squamous Cell Carcinoma
by Daphne Mytilineos, Jasmin Ezić, Adrian von Witzleben, Joannis Mytilineos, Ramin Lotfi, Daniel Fürst, Chrysanthi Tsamadou, Marie-Nicole Theodoraki, Angelika Oster, Gunnar Völkel, Hans A. Kestler, Cornelia Brunner, Patrick J. Schuler, Johannes Doescher, Thomas K. Hoffmann and Simon Laban
Int. J. Mol. Sci. 2020, 21(17), 5990; https://doi.org/10.3390/ijms21175990 - 20 Aug 2020
Cited by 15 | Viewed by 2101
Abstract
Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) [...] Read more.
Cytokines and immune mediators play an important role in the communication between immune cells guiding their response to infectious diseases or cancer. In this study, a comprehensive longitudinal analysis of serum cytokines and immune mediators in head and neck squamous cell carcinoma (HNSCC) patients was performed. In a prospective, non-interventional, longitudinal study, blood samples from 22 HNSCC patients were taken at defined time points (TP) before, during, and every 3 months after completion of (chemo)radio)therapy (CRT/RT) until 12 months after treatment. Serum concentrations of 17 cytokines/immune mediators and High-Mobility-Group-Protein B1 (HMGB1) were measured by fluorescent bead array and ELISA. Concentrations of sFas were significantly elevated during and after CRT/RT, whereas perforin levels were significantly decreased after CRT/RT. Levels of MIP-1β and Granzyme B differed significantly during CRT/RT by HPV status. Increased HMGB1 levels were observed at recurrence, accompanied by high levels of IL-4 and IL-10. The sFas increase and simultaneous perforin decrease may indicate an impaired immune cell function during adjuvant radiotherapy. Increased levels of pro-inflammatory cytokines in HPV+ compared to HPV− patients seem to reflect the elevated immunogenicity of HPV-positive tumors. High levels of HMGB1 and anti-inflammatory cytokines at recurrence may be interpreted as a sign of immune evasion. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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9 pages, 506 KiB  
Article
IGF2BP2 Polymorphisms Are Associated with Clinical Characteristics and Development of Oral Cancer
by Chia-Hsuan Chou, Chien-Yuan Chang, Hsueh-Ju Lu, Min-Chien Hsin, Mu-Kuan Chen, Hsien-Cheng Huang, Chia-Ming Yeh, Chiao-Wen Lin and Shun-Fa Yang
Int. J. Mol. Sci. 2020, 21(16), 5662; https://doi.org/10.3390/ijms21165662 - 07 Aug 2020
Cited by 22 | Viewed by 2313
Abstract
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is associated with insulin resistance, lipid metabolism, and tumorigenesis. However, the association between the IGF2BP2 polymorphism and oral cancer risk remains unclear. We recruited 1349 male patients with oral cancer and 1198 cancer-free controls. Three [...] Read more.
Insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2) is associated with insulin resistance, lipid metabolism, and tumorigenesis. However, the association between the IGF2BP2 polymorphism and oral cancer risk remains unclear. We recruited 1349 male patients with oral cancer and 1198 cancer-free controls. Three single nucleotide polymorphisms IGF2BP2 rs11705701, rs4402960, and rs1470579 were assessed using real-time polymerase chain reaction. The results indicate that the male patients with oral cancer and with the rs11705701 GA+AA, rs4402960 GT+TT, and rs1470579 AC+CC genotypes had increased risk of advanced clinical stage, larger tumor, and progression of lymph node metastasis compared with those with wild-type IGF2BP2. Moreover, according to The Cancer Genome Atlas dataset, high expression of the IGF2BP2 gene is associated with poor survival in patients with head and neck squamous cell carcinoma. In conclusion, our results suggest that IGF2BP2 polymorphisms are associated with less favorable oral cancer clinical characteristics. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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13 pages, 5627 KiB  
Article
NR2F6 as a Prognostic Biomarker in HNSCC
by Luise Klapper, Julika Ribbat-Idel, Patrick Kuppler, Finn-Ole Paulsen, Karl-Ludwig Bruchhage, Dirk Rades, Anne Offermann, Jutta Kirfel, Barbara Wollenberg, Christian Idel and Sven Perner
Int. J. Mol. Sci. 2020, 21(15), 5527; https://doi.org/10.3390/ijms21155527 - 01 Aug 2020
Cited by 15 | Viewed by 2736
Abstract
Head and neck squamous cell carcinoma (HNSCC)is the 6th most common cancer in humans worldwide and is associated with a poor prognosis for patients. NR2F6 has been identified as an immune checkpoint molecule in tumor-infiltrating T lymphocytes and is associated with a poor [...] Read more.
Head and neck squamous cell carcinoma (HNSCC)is the 6th most common cancer in humans worldwide and is associated with a poor prognosis for patients. NR2F6 has been identified as an immune checkpoint molecule in tumor-infiltrating T lymphocytes and is associated with a poor prognostic outcome in various cancers. The prognostic value of NR2F6 in HNSCC has not been described yet. We used a large, representative and clinically well-characterized cohort of 383 HNSCC patients, of which 22.4% developed a local recurrence. The NR2F6 expression was analyzed by using immunohistochemistry and was afterward correlated with clinical characteristics and clinicopathological features of HNSCC patients. Primary tumors from patients who develop a local recurrence have a higher NR2F6 expression than primary tumors which do not develop a local recurrence. Furthermore, a high NR2F6 expression is associated with poorer recurrence-free survival, although there is no correlation with overall survival. NR2F6 expression is independent of the T stage and UICC stage. NR2F6 might be a new prognostic biomarker for the early detection of local recurrences in HNSCC patients. Therefore, it may help to improve the recognition of patients who would benefit from more frequent follow-up examinations. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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14 pages, 4158 KiB  
Article
CDK19 as a Potential HPV-Independent Biomarker for Recurrent Disease in HNSCC
by Finn-Ole Paulsen, Christian Idel, Julika Ribbat-Idel, Patrick Kuppler, Luise Klapper, Dirk Rades, Karl-Ludwig Bruchhage, Barbara Wollenberg, Johannes Brägelmann, Sven Perner and Anne Offermann
Int. J. Mol. Sci. 2020, 21(15), 5508; https://doi.org/10.3390/ijms21155508 - 31 Jul 2020
Cited by 7 | Viewed by 2549
Abstract
The Mediator complex is a central integrator of transcription and a hub for the regulation of gene expression. Cyclin dependent kinase (CDK) 19 and its paralog CDK8 are part of its kinase domain and contribute to cancer progression in different cancer entities. STAT1 [...] Read more.
The Mediator complex is a central integrator of transcription and a hub for the regulation of gene expression. Cyclin dependent kinase (CDK) 19 and its paralog CDK8 are part of its kinase domain and contribute to cancer progression in different cancer entities. STAT1 is an important immune modulator and a downstream substrate of CDK8/CDK19 mediated phosphorylation. So far, little is known about CDK19’s role in head and neck squamous cell carcinoma (HNSCC) progression, its link to STAT1 activity, and related immune modulation. Immunohistochemistry for CDK19, activated pSTAT1, and PD-L1, known to be affected by STAT1, was conducted on samples of 130 primary tumors, 71 local recurrences, 32 lymph node metastases, and 25 distant metastases of HNSCC. Compared to primary tumors, CDK19 is overexpressed in local recurrences and distant metastases as well as in primary tumors that developed local recurrence after initial therapy. Patients with high-CDK19-expressing primary tumors have a significantly shorter disease-free survival. CDK19 expression correlates with pSTAT1 expression in primary tumors associated with recurrent disease, local recurrent tumors, lymph node metastases, and distant metastases. pSTAT1 expression correlates with PD-L1 expression in recurrent tumors. Our findings identify CDK19 as a potential biomarker in HNSCC to predict recurrent disease and support recent developments to target CDK19 and its paralog CDK8 in advanced cancer. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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17 pages, 1129 KiB  
Article
PD-L1 Expression and a High Tumor Infiltrate of CD8+ Lymphocytes Predict Outcome in Patients with Oropharyngeal Squamous Cells Carcinoma
by Nora Wuerdemann, Sibel E. Gültekin, Katharina Pütz, Claus Wittekindt, Christian U. Huebbers, Shachi J. Sharma, Hans Eckel, Anna B. Schubotz, Stefan Gattenlöhner, Reinhard Büttner, Ernst-Jan Speel, Jens P. Klussmann, Steffen Wagner and Alexander Quaas
Int. J. Mol. Sci. 2020, 21(15), 5228; https://doi.org/10.3390/ijms21155228 - 23 Jul 2020
Cited by 19 | Viewed by 3654
Abstract
Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (–) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV– OPSCC is expected. The purpose of this study [...] Read more.
Carcinogenesis of human papillomavirus (HPV)-related (+) oropharyngeal squamous cell carcinoma (OPSCC) differs from HPV-negative (–) OPSCC. HPV-related immune-escape-mechanism could be responsible for the development and progression of HPV+ tumors and an immunophenotype different from HPV– OPSCC is expected. The purpose of this study was to analyze the expression of programmed cell death protein 1 ligand 1 (PD-L1) and its prognostic relevance in relation to CD8+ tumor infiltrating lymphocytes (TILs) and the major histocompatibility complex (MHC) I expression in OPSCC. We quantified PD-L1 expression on tumor cells (TC) and macrophages and MHC I expression in association to CD8+ TILs by immunohistochemistry on tissue microarray derived from 171 HPV+/-OPSCC. HPV-status was determined by p16INK4a immunohistochemistry/HPV-DNA detection. Presence of CD8+ TILs, PD-L1 expression on TC, and a more frequent loss of MHC I in HPV+ compared to HPV- OPSCC was detected. A high amount of CD8+ TILs in the whole cohort and in HPV+ OPSCC and PD-L1 expression on TC in HPV- OPSCC was associated with favorable overall survival. There was a trend for an improved outcome according to PD-L1 expression (macrophages) in HPV+ OPSCC without reaching statistical significance. CD8+ TILs and PD-L1-expression have prognostic impact in OPSCC and might present useful biomarkers for predicting clinical outcome and personalized therapy concepts. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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17 pages, 2680 KiB  
Article
Immune Checkpoint Expression on Immune Cells of HNSCC Patients and Modulation by Chemo- and Immunotherapy
by Lisa K. Puntigam, Sandra S. Jeske, Marlies Götz, Jochen Greiner, Simon Laban, Marie-Nicole Theodoraki, Johannes Doescher, Stephanie E. Weissinger, Cornelia Brunner, Thomas K. Hoffmann and Patrick J. Schuler
Int. J. Mol. Sci. 2020, 21(15), 5181; https://doi.org/10.3390/ijms21155181 - 22 Jul 2020
Cited by 16 | Viewed by 3136
Abstract
Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood [...] Read more.
Endogenous control mechanisms, including immune checkpoints and immunosuppressive cells, are exploited in the process of tumorigenesis to weaken the anti-tumor immune response. Cancer treatment by chemotherapy or immune checkpoint inhibition can lead to changes of checkpoint expression, which influences therapy success. Peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) were isolated from head and neck squamous cell carcinoma (HNSCC) patients (n = 23) and compared to healthy donors (n = 23). Immune checkpoint expression (programmed cell death ligand 1 (PD-1), tumor necrosis factor receptor (TNFR)-related (GITR), CD137, tumor necrosis factor receptor superfamily member 4 (TNFRSF4) (OX40), t-cell immunoglobulin and mucin-domain containing-3 (TIM3), B- and T-lymphocyte attenuator (BTLA), lymphocyte-activation gene 3 (LAG3)) was determined on immune cells by flow cytometry. PD-L1 expression was detected on tumor tissue by immunohistochemistry. Immune cells were treated with immuno- and chemotherapeutics to investigate treatment-specific change in immune checkpoint expression, in vitro. Specific changes of immune checkpoint expression were identified on PBL and TIL of HNSCC patients compared to healthy donors. Various chemotherapeutics acted differently on the expression of immune checkpoints. Changes of checkpoint expression were significantly less pronounced on regulatory T cells compared to other lymphocyte populations. Nivolumab treatment significantly reduced the receptor PD-1 on all analyzed T cell populations, in vitro. The specific immune checkpoint expression patterns in HNSCC patients and the investigated effects of immunomodulatory agents may improve the development and efficacy of targeted immunotherapy. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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11 pages, 1777 KiB  
Article
Impact of SRY-Box Transcription Factor 11 Gene Polymorphisms on Oral Cancer Risk and Clinicopathologic Characteristics
by Chia-Ming Yeh, Chiao-Wen Lin, Hsueh-Ju Lu, Chun-Yi Chuang, Chia-Hsuan Chou, Shun-Fa Yang and Mu-Kuan Chen
Int. J. Mol. Sci. 2020, 21(12), 4468; https://doi.org/10.3390/ijms21124468 - 23 Jun 2020
Cited by 2 | Viewed by 1950
Abstract
Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role [...] Read more.
Oral cancer is among the most common cancers worldwide and has become a major global health problem because of its relatively high morbidity and mortality rates. The sex-determining region on the Y-chromosome-related high-mobility-group box (SOX) transcription factor 11 (SOX11) plays a key role in human development and differentiation and is frequently increased in various human cancers. However, the clinical significance of SOX11 polymorphisms in oral cancer and their association with oral cancer risk are unclear. In this study, we included 1196 patients with oral cancer and 1200 controls. Real-time polymerase chain reaction was applied to analyze three SOX11 single-nucleotide polymorphisms (rs77996007, rs66465560, and rs68114586). Our results shown that SOX11 polymorphisms carriers with betel quid chewing were found to have an 8.38- to 9.23-fold risk to have oral cancer compared to SOX11 wild-type carriers without betel quid chewing. Furthermore, oral cancer patients who carried SOX11 rs77996007 “TC + CC” variants were significantly associated with large tumor size (AOR, 1.324; 95% CI, 1.047–1.674; p = 0.019). Moreover, a database analysis using the Cancer Genome Atlas suggested that SOX11 mRNA expression was high during the tumor development process. In conclusion, our results suggest that SOX11 rs77996007 is involved in oral cancer progression and clinical characteristics. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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10 pages, 1780 KiB  
Article
EVI1 as a Marker for Lymph Node Metastasis in HNSCC
by Christian Idel, Julika Ribbat-Idel, Patrick Kuppler, Rosemarie Krupar, Anne Offermann, Wenzel Vogel, Dirk Rades, Jutta Kirfel, Barbara Wollenberg and Sven Perner
Int. J. Mol. Sci. 2020, 21(3), 854; https://doi.org/10.3390/ijms21030854 - 28 Jan 2020
Cited by 19 | Viewed by 3196
Abstract
Background: HNSCC is the sixth most common cancer in humans and has still a very poor prognosis. The treatment methods so far are very often associated with mutilation and impairment in the quality of life. Except for p16 expression, there are no reliable [...] Read more.
Background: HNSCC is the sixth most common cancer in humans and has still a very poor prognosis. The treatment methods so far are very often associated with mutilation and impairment in the quality of life. Except for p16 expression, there are no reliable prognostic markers in HNSCC so far. Ecotropic Viral Integration Site 1 (EVI1) is a well-described prognostic marker in leukemia and different types of solid cancers. In these, a high EVI1 expression is associated with a poor prognosis. In HNSCC, it is not known so far if EVI1 has any prognostic relevance. Materials and Methods: We used our representative tissue cohort of 389 primary HNSCCs, of which 57.2% had one or more lymph node metastases. Here EVI1 expression was analyzed via immunohistochemistry and correlated with the clinical characteristics of these patients. Results: Although in HNSCC EVI1 expression does not predict poor survival, a high EVI1 expression in the primary tumor correlates with a lymph node metastatic disease. Conclusion: Consequently, EVI1 may serve as a biomarker to predict an occult lymph node metastasis in a clinical nodal negative (cN0) HNSCC. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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Review

Jump to: Editorial, Research

17 pages, 526 KiB  
Review
Immune Escape Mechanisms and Their Clinical Relevance in Head and Neck Squamous Cell Carcinoma
by Barbara Seliger, Chiara Massa, Bo Yang, Daniel Bethmann, Matthias Kappler, Alexander Walter Eckert and Claudia Wickenhauser
Int. J. Mol. Sci. 2020, 21(19), 7032; https://doi.org/10.3390/ijms21197032 - 24 Sep 2020
Cited by 23 | Viewed by 3280
Abstract
Immunotherapy has been recently approved for the treatment of relapsed and metastatic human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC). However, the response of patients is limited and the overall survival remains short with a low rate [...] Read more.
Immunotherapy has been recently approved for the treatment of relapsed and metastatic human papilloma virus (HPV) positive and negative head and neck squamous cell carcinoma (HNSCC). However, the response of patients is limited and the overall survival remains short with a low rate of long-term survivors. There exists growing evidence that complex and partially redundant immune escape mechanisms play an important role for the low efficacy of immunotherapies in this disease. These are caused by diverse complex processes characterized by (i) changes in the expression of immune modulatory molecules in tumor cells, (ii) alterations in the frequency, composition and clonal expansion of immune cell subpopulations in the tumor microenvironment and peripheral blood leading to reduced innate and adaptive immune responses, (iii) impaired homing of immune cells to the tumor site as well as (iv) the presence of immune suppressive soluble and physical factors in the tumor microenvironment. We here summarize the major immune escape strategies of HNSCC lesions, highlight pathways, and molecular targets that help to attenuate HNSCC-induced immune tolerance, affect the selection and success of immunotherapeutic approaches to overcome resistance to immunotherapy by targeting immune escape mechanisms and thus improve the HNSCC patients’ outcome. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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22 pages, 1579 KiB  
Review
The Emerging Role of Exosomes in Diagnosis, Prognosis, and Therapy in Head and Neck Cancer
by Linda Hofmann, Sonja Ludwig, Julius M. Vahl, Cornelia Brunner, Thomas K. Hoffmann and Marie-Nicole Theodoraki
Int. J. Mol. Sci. 2020, 21(11), 4072; https://doi.org/10.3390/ijms21114072 - 06 Jun 2020
Cited by 48 | Viewed by 15051
Abstract
Exosomes, the smallest group of extracellular vesicles, carry proteins, miRNA, mRNA, DNA, and lipids, which they efficiently deliver to recipient cells, generating a communication network. Exosomes strongly contribute to the immune suppressive tumor microenvironment of head and neck squamous cell carcinomas (HNSCC). Isolation [...] Read more.
Exosomes, the smallest group of extracellular vesicles, carry proteins, miRNA, mRNA, DNA, and lipids, which they efficiently deliver to recipient cells, generating a communication network. Exosomes strongly contribute to the immune suppressive tumor microenvironment of head and neck squamous cell carcinomas (HNSCC). Isolation of exosomes from HNSCC cell culture or patient’s plasma allows for analyzing their molecular cargo and functional role in immune suppression and tumor progression. Immune affinity-based separation of different exosome subsets, such as tumor-derived or T cell-derived exosomes, from patient’s plasma simultaneously informs about tumor status and immune dysfunction. In this review, we discuss the recent understanding of how exosomes behave in the HNSCC tumor microenvironment and why they are promising liquid biomarkers for diagnosis, prognosis, and therapy in HNSCC. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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12 pages, 260 KiB  
Review
Special Issue about Head and Neck Cancers: HPV Positive Cancers
by Panagiota Economopoulou, Ioannis Kotsantis and Amanda Psyrri
Int. J. Mol. Sci. 2020, 21(9), 3388; https://doi.org/10.3390/ijms21093388 - 11 May 2020
Cited by 36 | Viewed by 4615
Abstract
The oropharynx has become the leading primary site for Human Papilloma Virus (HPV)-associated head and neck cancer. HPV positive oropharyngeal squamous cell carcinoma (HPV+ OSCC) has emerged as an epidemic not easily recognized by many physicians, resulting in delays in diagnosis and management. [...] Read more.
The oropharynx has become the leading primary site for Human Papilloma Virus (HPV)-associated head and neck cancer. HPV positive oropharyngeal squamous cell carcinoma (HPV+ OSCC) has emerged as an epidemic not easily recognized by many physicians, resulting in delays in diagnosis and management. HPV+ OSCC traditionally refers to younger, healthier patients with high economic status and high-risk sexual behavior and is related to improved prognosis. De-intensification strategies are being evaluated in ongoing clinical trials and if validated, might help spare severe morbidity associated with current cisplatin-based chemoradiotherapy, which is the standard of care for all patients with locally advanced head and neck cancer. On the other hand, whether HPV status represents an important prognostic factor for non-oropharyngeal sites remains to be elucidated. Full article
(This article belongs to the Special Issue Squamous Cell Cancer of the Head and Neck—Time to Arrive in the 21st Century of Oncology)
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