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21 pages, 2411 KiB

Open AccessArticle

ANO1 Expression Orchestrates p27Kip1/MCL1-Mediated Signaling in Head and Neck Squamous Cell Carcinoma

by Artemis Filippou, Henna Pehkonen, Piia-Riitta Karhemo, Juho Väänänen, Anni I. Nieminen, Juha Klefström, Reidar Grénman, Antti A. Mäkitie, Heikki Joensuu and Outi Monni

Cancers 2021, 13(5), 1170; https://doi.org/10.3390/cancers13051170 - 9 Mar 2021

Cited by 12 | Viewed by 3699

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is a heterogeneous group of tumors that derive from the mucosal epithelium of the upper aerodigestive tract and present high mortality rate. Lack of efficient targeted-therapies and biomarkers towards patients’ stratification are caveats in the disease treatment. Anoctamin 1 (ANO1) gene is amplified in 30% of HNSCC cases. Evidence suggests involvement of ANO1 in proliferation, migration, and evasion of apoptosis; however, the exact mechanisms remain elusive. Aim of this study was to unravel the ANO1-dependent transcriptional programs and expand the existing knowledge of ANO1 contribution to oncogenesis and drug response in HNSCC. We cultured two HNSCC cell lines established from primary tumors harboring amplification and high expression of ANO1 in three-dimensional collagen. Differential expression analysis of ANO1-depleted HNSCC cells demonstrated downregulation of MCL1 and simultaneous upregulation of p27^Kip1 expression. Suppressing ANO1 expression led to redistribution of p27^Kip1 from the cytoplasm to the nucleus and associated with a cell cycle arrested phenotype. ANO1 silencing or pharmacological inhibition resulted in reduction of cell viability and ANO1 protein levels, as well as suppression of pro-survival BCL2 family proteins. Collectively, these data provide insights of ANO1 involvement in HNSCC carcinogenesis and support the rationale that ANO1 is an actionable drug target. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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23 pages, 28387 KiB

Open AccessArticle

Mi-RNA-888-5p Is Involved in S-Adenosylmethionine Antitumor Effects in Laryngeal Squamous Cancer Cells

by Martina Pagano, Laura Mosca, Francesca Vitiello, Concetta Paola Ilisso, Alessandra Coppola, Luigi Borzacchiello, Luigi Mele, Francesca Pia Caruso, Michele Ceccarelli, Michele Caraglia, Giovanna Cacciapuoti and Marina Porcelli

Cancers 2020, 12(12), 3665; https://doi.org/10.3390/cancers12123665 - 7 Dec 2020

Cited by 14 | Viewed by 2846

Abstract

(1) Purpose: The methyl donor S-Adenosylmethionine (AdoMet) has been widely explored as a therapeutic compound, and its application-alone or in combination with other molecules-is emerging as a potential effective strategy for the treatment and chemoprevention of tumours. In this study, we investigated the [...] Read more.

(1) Purpose: The methyl donor S-Adenosylmethionine (AdoMet) has been widely explored as a therapeutic compound, and its application-alone or in combination with other molecules-is emerging as a potential effective strategy for the treatment and chemoprevention of tumours. In this study, we investigated the antitumor activity of AdoMet in Laryngeal Squamous Cell Carcinoma (LSCC), exploring the underlying mechanisms. (2) Results: We demonstrated that AdoMet induced ROS generation and triggered autophagy with a consistent increase in LC3B-II autophagy-marker in JHU-SCC-011 and HNO210 LSCC cells. AdoMet induced ER-stress and activated UPR signaling through the upregulation of the spliced form of XBP1 and CHOP. To gain new insights into the molecular mechanisms underlying the antitumor activity of AdoMet, we evaluated the regulation of miRNA expression profile and we found a downregulation of miR-888-5p. We transfected LSCC cells with miR-888-5p inhibitor and exposed the cells to AdoMet for 48 and 72 h. The combination of AdoMet with miR-888-5p inhibitor synergistically induced both apoptosis and inhibited cell migration paralleled by the up-regulation of MYCBP and CDH1 genes and of their targets. (3) Conclusion: Overall, these data highlighted that epigenetic reprogramming of miRNAs by AdoMet play an important role in inhibiting apoptosis and migration in LSCC cell lines. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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20 pages, 4167 KiB

Open AccessArticle

A Combined Systemic Strategy for Overcoming Cisplatin Resistance in Head and Neck Cancer: From Target Identification to Drug Discovery

by Yin-Ju Chen, Guo-Rung You, Meng-Yu Lai, Long-Sheng Lu, Chang-Yu Chen, Lai-Lei Ting, Hsin-Lun Lee, Yuzuka Kanno, Jeng-Fong Chiou and Ann-Joy Cheng

Cancers 2020, 12(11), 3482; https://doi.org/10.3390/cancers12113482 - 23 Nov 2020

Cited by 9 | Viewed by 4016

Abstract

Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines [...] Read more.

Cisplatin is the first-line chemotherapy agent for head and neck cancer (HNC), but its therapeutic effects are hampered by its resistance. In this study, we employed systemic strategies to overcome cisplatin resistance (CR) in HNC. CR cells derived from isogenic HNC cell lines were generated. The CR related hub genes, functional mechanisms, and the sensitizing candidates were globally investigated by transcriptomic and bioinformatic analyses. Clinically, the prognostic significance was assessed by the Kaplan–Meier method. Cellular and molecular techniques, including cell viability assay, tumorsphere formation assay, RT-qPCR, and immunoblot, were used. Results showed that these CR cells possessed highly invasive and stem-like properties. A total of 647 molecules was identified, and the mitotic division exhibited a novel functional mechanism significantly related to CR. A panel of signature molecules, MSRB3, RHEB, ULBP1, and spindle pole body component 25 (SPC25), was found to correlate with poor prognosis in HNC patients. SPC25 was further shown as a prominent molecule, which markedly suppressed cancer stemness and attenuated CR after silencing. Celastrol, a nature extract compound, was demonstrated to effectively inhibit SPC25 expression and reverse CR phenotype. In conclusion, the development of SPC25 inhibitors, such as the application of celastrol, maybe a novel strategy to sensitize cisplatin for the treatment of refractory HNC. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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17 pages, 5324 KiB

Open AccessArticle

Immune Phenotypes of Nasopharyngeal Cancer

by Johan S. Nilsson, Aastha Sobti, Sabine Swoboda, Jonas S. Erjefält, Ola Forslund, Malin Lindstedt and Lennart Greiff

Cancers 2020, 12(11), 3428; https://doi.org/10.3390/cancers12113428 - 18 Nov 2020

Cited by 10 | Viewed by 3656

Abstract

Nasopharyngeal cancer (NPC) features intralesional immune cells, but data are lacking on presence/distribution of T-cells and dendritic cells (DCs). Based on intralesional distribution of lymphocytes, a series of NPC biopsies (n = 48) were classified into “inflamed”, “excluded”, and “deserted” phenotypes. In [...] Read more.

Nasopharyngeal cancer (NPC) features intralesional immune cells, but data are lacking on presence/distribution of T-cells and dendritic cells (DCs). Based on intralesional distribution of lymphocytes, a series of NPC biopsies (n = 48) were classified into “inflamed”, “excluded”, and “deserted” phenotypes. In addition, CD8+ T-cells and CD207+ DCs were quantified. The data were analyzed in relation to Epstein–Barr virus-encoded small RNA (EBER), Epstein-Barr virus (EBV) DNA, and survival. Separately, data on gene expression from a public database were analyzed. 61.7% of NPC lesions were “inflamed”, 29.8% were “excluded”, and 8.5% were “deserted”. While CD8+ cells were present in cancer cell areas and in surrounding stroma, CD207+ cells were observed largely in cancer cell areas. High CD8+ T-cell presence was associated with EBV+ disease, but no such pattern was observed for CD207+ DCs. There was a difference in disease-free survival in favor of “inflamed” over “excluded” NPC. Gene expression analysis revealed differences between NPC and control tissue (e.g., with regard to interferon activity) as well as between subgroups of NPC based on CD8 expression (high vs. low). In conclusion, NPC lesions are heterogeneous with regard to distribution of CD8+ T-cells and CD207+ DCs. NPC can be classified into immune phenotypes that carry prognostic information. CD207+ DCs may represent a target for immunotherapy with potential to facilitate the antigen cross-presentation necessary to execute cytotoxic T-lymphocyte responses. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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17 pages, 1748 KiB

Open AccessArticle

Complex Mandibular Reconstruction for Head and Neck Squamous Cell Carcinoma—The Ongoing Challenge in Reconstruction and Rehabilitation

by Tomislav A. Zrnc, Josip Tomic, Peter V. Tomazic, Hamid Hassanzadeh, Matthias Feichtinger, Wolfgang Zemann, Philipp Metzler and Mauro Pau

Cancers 2020, 12(11), 3198; https://doi.org/10.3390/cancers12113198 - 30 Oct 2020

Cited by 5 | Viewed by 5516

Abstract

Large head and neck squamous cell carcinoma (HNSCC) tumors affecting the mandible require a versatile reconstruction to maintain form, function, and quality of life. Large defect reconstruction of soft and hard tissue in the head and neck necessitates, at best, one vascular system [...] Read more.

Large head and neck squamous cell carcinoma (HNSCC) tumors affecting the mandible require a versatile reconstruction to maintain form, function, and quality of life. Large defect reconstruction of soft and hard tissue in the head and neck necessitates, at best, one vascular system including various tissues by large dimensions. The subscapular flap system seems to meet these standards. A retrospective study was conducted focusing on clinical data, including an analysis of the quality of life with the European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaires, (QLQ-C30 and QLQ-H&N43). A total of 154 patients (122 males, 32 females; age range: 31–71 years, mean: 54.5 years) treated at our department from 1983 through to 2019 were included. Of the subscapular system free flaps (SFFs), 147 were based on the angular artery branch of the thoracodorsal pedicle (95.45%), and the remaining seven cases (4.55%) were lateral scapular border flaps. Mean mandible defect length was 7.3 cm. The mean skin paddle dimension was 86.8 cm². The most common recipient artery was the thyroid superior artery (79.22%). Major postoperative complications occurred in 13 patients (8.44%). This study confirms that SFFs offer excellent soft and hard tissue quality, component independence, a large arc of rotation length, and a large gauge of pedicle, making them the gold standard for the reconstruction of large composite defects of mandibular HNSCC tumors. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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26 pages, 945 KiB

Open AccessArticle

Comprehensive Analysis of Tumour Sub-Volumes for Radiomic Risk Modelling in Locally Advanced HNSCC

by Stefan Leger, Alex Zwanenburg, Karoline Leger, Fabian Lohaus, Annett Linge, Andreas Schreiber, Goda Kalinauskaite, Inge Tinhofer, Nika Guberina, Maja Guberina, Panagiotis Balermpas, Jens von der Grün, Ute Ganswindt, Claus Belka, Jan C. Peeken, Stephanie E. Combs, Simon Boeke, Daniel Zips, Christian Richter, Mechthild Krause, Michael Baumann, Esther G.C. Troost and Steffen Löck Show full author list Hide full author list

Cancers 2020, 12(10), 3047; https://doi.org/10.3390/cancers12103047 - 19 Oct 2020

Cited by 19 | Viewed by 3399

Abstract

Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTV

_{entire}

). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the [...] Read more.

Imaging features for radiomic analyses are commonly calculated from the entire gross tumour volume (GTV

_{entire}

). However, tumours are biologically complex and the consideration of different tumour regions in radiomic models may lead to an improved outcome prediction. Therefore, we investigated the prognostic value of radiomic analyses based on different tumour sub-volumes using computed tomography imaging of patients with locally advanced head and neck squamous cell carcinoma. The GTV

_{entire}

was cropped by different margins to define the rim and the corresponding core sub-volumes of the tumour. Subsequently, the best performing tumour rim sub-volume was extended into surrounding tissue with different margins. Radiomic risk models were developed and validated using a retrospective cohort consisting of 291 patients in one of the six Partner Sites of the German Cancer Consortium Radiation Oncology Group treated between 2005 and 2013. The validation concordance index (C-index) averaged over all applied learning algorithms and feature selection methods using the GTV

_{entire}

achieved a moderate prognostic performance for loco-regional tumour control (C-index: 0.61 ± 0.04 (mean ± std)). The models based on the 5 mm tumour rim and on the 3 mm extended rim sub-volume showed higher median performances (C-index: 0.65 ± 0.02 and 0.64 ± 0.05, respectively), while models based on the corresponding tumour core volumes performed less (C-index: 0.59 ± 0.01). The difference in C-index between the 5 mm tumour rim and the corresponding core volume showed a statistical trend (p = 0.10). After additional prospective validation, the consideration of tumour sub-volumes may be a promising way to improve prognostic radiomic risk models. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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18 pages, 3929 KiB

Open AccessArticle

Cell-Free HPV-DNA as a Biomarker for Oropharyngeal Squamous Cell Carcinoma—A Step Towards Personalized Medicine?

by Nora Wuerdemann, Rishabh Jain, Anne Adams, Ernst-Jan M. Speel, Steffen Wagner, Simon A. Joosse and Jens P. Klussmann

Cancers 2020, 12(10), 2997; https://doi.org/10.3390/cancers12102997 - 15 Oct 2020

Cited by 38 | Viewed by 6118

Abstract

Global incidences of oropharyngeal squamous cell carcinoma (OPSCC) are rising due to an association with high-risk human papillomavirus (HPV). Although there is an improved overall survival of HPV-related OPSCC; up to 25% of the patients develop recurrent or distant metastatic disease with a [...] Read more.

Global incidences of oropharyngeal squamous cell carcinoma (OPSCC) are rising due to an association with high-risk human papillomavirus (HPV). Although there is an improved overall survival of HPV-related OPSCC; up to 25% of the patients develop recurrent or distant metastatic disease with a fatal outcomes. Biomarkers to monitor this disease are not established. This meta-analysis reviews the role of cell-free HPV DNA in liquid biopsy (LB) as a biomarker for HPV-related OPSCC. Pubmed, Livivo, and Cochrane Library databases were searched from inception to August, 2020. All studies were analyzed by Meta-DiSc 1.4 and Stata 16.0 statistical software. In total, 16 studies were considered for systematic review, whereas 11 studies met inclusion criteria for meta-analysis, respectively. Pooled sensitivity of cfHPV-DNA at first diagnosis and during follow-up was 0.81 (95% CI; 0.78–0.84) and 0.73 (95% CI; 0.57–0.86), while pooled specificity was 0.98 (95% CI; 0.96–0.99) and 1 (95% CI; 0.99–1). The diagnostic odds ratio (DOR) at first diagnosis was 200.60 (95% CI; 93.31–431.22) and 300.31 (95% CI; 60.94–1479.88) during follow-up. The area under the curve (AUC) of summary receiver operating characteristic (SROC) was 0.99 at first diagnosis and 1.00 during follow-up, respectively. In conclusion, cfHPV-DNA presents a potential biomarker with high specificity in patients with HPV-related OPSCC. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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21 pages, 3066 KiB

Open AccessArticle

CTEN Induces Tumour Cell Invasion and Survival and Is Prognostic in Radiotherapy-Treated Head and Neck Cancer

by Jason C. Fleming, Jeongmin Woo, Karwan Moutasim, Christopher J. Hanley, Steven J. Frampton, Oliver Wood, Matthew Ward, Christopher H. Woelk, Christian H. Ottensmeier, Sassan Hafizi, Dae Kim and Gareth J. Thomas

Cancers 2020, 12(10), 2963; https://doi.org/10.3390/cancers12102963 - 13 Oct 2020

Cited by 8 | Viewed by 3475

Abstract

Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is a heterogenous disease treated with surgery and/or (chemo) radiotherapy, but up to 50% of patients with late-stage disease develop locoregional recurrence. Determining the mechanisms underpinning treatment resistance could identify new therapeutic targets and aid treatment selection. C-terminal tensin-like (CTEN) is a member of the tensin family, upregulated in several cancers, although its expression and function in HNSCC are unknown. We found that CTEN is commonly upregulated in HNSCC, particularly HPV^−ve tumours. In vitro CTEN was upregulated in HPV^−ve (n = 5) and HPV^+ve (n = 2) HNSCC cell lines. Stable shRNA knockdown of CTEN in vivo significantly reduced tumour growth (SCC-25), and functional analyses in vitro showed that CTEN promoted tumour cell invasion, colony formation and growth in 3D-culture (SCC-25, Detroit 562). RNA sequencing of SCC-25 cells following CTEN siRNA knockdown identified 349 differentially expressed genes (logFC > 1, p < 0.05). Gene ontology analysis highlighted terms relating to cell locomotion and apoptosis, consistent with in vitro findings. A membrane-based antibody array confirmed that CTEN regulated multiple apoptosis-associated proteins, including HSP60 and cleaved caspase-3. Notably, in a mixed cohort of HPV^+ve and HPV^−ve HNSCC patients (n = 259), we found a significant, independent negative association of CTEN with prognosis, limited to those patients treated with (chemo)radiotherapy, not surgery, irrespective of human papillomavirus (HPV) status. These data show that CTEN is commonly upregulated in HNSCC and exerts several functional effects. Its potential role in modulating apoptotic response to therapy suggests utility as a predictive biomarker or radio-sensitising target. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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15 pages, 1915 KiB

Open AccessArticle

The Additional Value of Ultrafast DCE-MRI to DWI-MRI and 18F-FDG-PET to Detect Occult Primary Head and Neck Squamous Cell Carcinoma

by Roland M. Martens, Ruud van der Stappen, Thomas Koopman, Daniel P. Noij, Emile F. Comans, Gerben J. Zwezerijnen, Marije R. Vergeer, C. René Leemans, Remco de Bree, Ronald Boellaard, Jonas A. Castelijns and Pim de Graaf

Cancers 2020, 12(10), 2826; https://doi.org/10.3390/cancers12102826 - 30 Sep 2020

Cited by 15 | Viewed by 2977

Abstract

To evaluate diagnostic accuracy of qualitative analysis and interobserver agreement of single ultrafast-DCE, DWI or ¹⁸F-FDG-PET and the combination of modalities for the detection of unknown primary tumor (UPT) in patients presenting with cervical lymph node metastasis from squamous cell carcinoma (SCC). [...] Read more.

To evaluate diagnostic accuracy of qualitative analysis and interobserver agreement of single ultrafast-DCE, DWI or ¹⁸F-FDG-PET and the combination of modalities for the detection of unknown primary tumor (UPT) in patients presenting with cervical lymph node metastasis from squamous cell carcinoma (SCC). Between 2014–2019, patients with histologically proven cervical lymph node metastasis of UPT SCC were prospectively included and underwent DWI, ultrafast-DCE, and ¹⁸F-FDG-PET/CT. Qualitative assessment was performed by two observers per modality. Interobserver agreement was calculated using the proportion specific agreement. Diagnostic accuracy of combined use of DWI, ultrafast-DCE and ¹⁸F-FDG-PET/CT was assessed. Twenty-nine patients were included (20 males. [68%], median age 60 years). Nine (31%) primary tumors remained occult. Ultrafast-DCE added reader confidence for suspicious locations (one additional true positive (5%), 2 decisive true malignant (10%). The per-location analysis showed highest specific positive agreement for ultrafast-DCE (77.6%). The per-location rating showed highest sensitivity (95%, 95%CI = 75.1–99.9, YI = 0.814) when either one of all modalities was scored positive, and 97.4% (95%CI = 93.5–99.3, YI = 0.774) specificity when co-detected on all. The per-patient analysis showed highest sensitivity (100%) for ¹⁸F-FDG-PET/CT (YI = 0.222) and either DWI or PET (YI = 0.111). Despite highest trends, no significant differences were found. The per-patient analysis showed highest specific positive agreement when co-detected on all modalities (55.6%, 95%CI = 21.2–86.3, YI = 0.456). Ultrafast-DCE showed potential to improve detection of unknown primary tumors in addition to DWI and ¹⁸F-FDG-PET/CT in patients with cervical squamous cell carcinoma lymph node metastasis. The combined use of ultrafast-DCE, DWI and ¹⁸F-FDG-PET/CT yielded highest sensitivity. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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14 pages, 2082 KiB

Open AccessArticle

Dual Inhibition of Autophagy and PI3K/AKT/MTOR Pathway as a Therapeutic Strategy in Head and Neck Squamous Cell Carcinoma

by Monique Bernard, Guillaume B. Cardin, Maxime Cahuzac, Tareck Ayad, Eric Bissada, Louis Guertin, Houda Bahig, Phuc Felix Nguyen-Tan, Edith Filion, Olivier Ballivy, Denis Soulieres, Francis Rodier and Apostolos Christopoulos

Cancers 2020, 12(9), 2371; https://doi.org/10.3390/cancers12092371 - 21 Aug 2020

Cited by 17 | Viewed by 3854

Abstract

Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC [...] Read more.

Genomic analyses of head and neck squamous cell carcinoma (HNSCC) have highlighted alterations in the phosphatidylinositol 3-kinase (PI3K) signaling pathway, presenting a therapeutic target for multiple ongoing clinical trials with PI3K or PI3K/MTOR inhibitors. However, these inhibitors can potentially increase autophagy in HNSCC and indirectly support cancer cell survival. Here, we sought to understand the relationship between the PI3K signaling pathway and autophagy during their dual inhibition in a panel of HNSCC cell lines. We used acridine orange staining, immunoblotting, and tandem sensor Red Fluorescent Protein- Green Fluorescent Protein-, microtubule-associated protein 1 light chain 3 beta (RFP-GFP-LC3B) expression analysis to show that PI3K inhibitors increase autophagosomes in HNSCC cells, but that chloroquine treatment effectively inhibits the autophagy that is induced by PI3K inhibitors. Using the Bliss independence model, we determined that the combination of chloroquine with PI3K inhibitors works in synergy to decrease cancer cell proliferation, independent of the PIK3CA status of the cell line. Our results indicate that a strategy focusing on autophagy inhibition enhances the efficacy of therapeutics already in clinical trials. Our results suggest a broader application for this combination therapy that can be promptly translated to in vivo studies. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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16 pages, 2651 KiB

Open AccessArticle

Circulating Exosomes Inhibit B Cell Proliferation and Activity

by Jan C. Schroeder, Lisa Puntigam, Linda Hofmann, Sandra S. Jeske, Inga J. Beccard, Johannes Doescher, Simon Laban, Thomas K. Hoffmann, Cornelia Brunner, Marie-Nicole Theodoraki and Patrick J. Schuler

Cancers 2020, 12(8), 2110; https://doi.org/10.3390/cancers12082110 - 29 Jul 2020

Cited by 26 | Viewed by 3611

Abstract

(1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by [...] Read more.

(1) Background: Head and neck squamous cell carcinoma (HNSCC) is characterized by a distinctive suppression of the anti-tumor immunity, both locally in the tumor microenvironment (TME) and the periphery. Tumor-derived exosomes mediate this immune suppression by directly suppressing T effector function and by inducing differentiation of regulatory T cells. However, little is known about the effects of exosomes on B cells. (2) Methods: Peripheral B cells from healthy donors and HNSCC patients were isolated and checkpoint receptor expression was analyzed by flow cytometry. Circulating exosomes were isolated from the plasma of HNSCC patients (n = 21) and healthy individuals (n = 10) by mini size-exclusion chromatography. B cells from healthy individuals were co-cultured with isolated exosomes for up to 4 days. Proliferation, viability, surface expression of checkpoint receptors, and intracellular signaling were analyzed in B cells by flow cytometry. (3) Results: Expression of the checkpoint receptors PD-1 and LAG3 was increased on B cells from HNSCC patients. The protein concentration of circulating exosomes was increased in HNSCC patients as compared to healthy donors. Both exosomes from healthy individuals and HNSCC patients inhibited B cell proliferation and survival, in vitro. Surface expression of inhibitory and stimulatory checkpoint receptors on B cells was modulated in co-culture with exosomes. In addition, an inhibitory effect of exosomes on B cell receptor (BCR) signaling was demonstrated in B cells. (4) Conclusions: Plasma-derived exosomes show inhibitory effects on the function of healthy B cells. Interestingly, these inhibitory effects are similar between exosomes from healthy individuals and HNSCC patients, suggesting a physiological B cell inhibitory role of circulating exosomes. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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15 pages, 2798 KiB

Open AccessArticle

Immune Suppressive Effects of Plasma-Derived Exosome Populations in Head and Neck Cancer

by Inga J. Beccard, Linda Hofmann, Jan C. Schroeder, Sonja Ludwig, Simon Laban, Cornelia Brunner, Ramin Lotfi, Thomas K. Hoffmann, Edwin K. Jackson, Patrick J. Schuler and Marie-Nicole Theodoraki

Cancers 2020, 12(7), 1997; https://doi.org/10.3390/cancers12071997 - 21 Jul 2020

Cited by 31 | Viewed by 4386

Abstract

Plasma-derived exosomes of head and neck squamous cell carcinoma (HNSCC) patients carry inhibitory factors mediating immune suppression. Separation of tumor-derived exosomes (TEX) and non-TEX may assist in a better understanding of their respective parental cells. Here, we evaluate the impact of TEX or [...] Read more.

Plasma-derived exosomes of head and neck squamous cell carcinoma (HNSCC) patients carry inhibitory factors mediating immune suppression. Separation of tumor-derived exosomes (TEX) and non-TEX may assist in a better understanding of their respective parental cells. Here, we evaluate the impact of TEX or hematopoietic-derived exosomes on immune suppression. We evaluated apoptosis in CD8+ T cells, conversion of CD4+ T cells to regulatory T cells (T_reg), and adenosine production by TEX, non-TEX, or total exosomes. Exosome protein cargo was significantly higher in total and CD45(−) exosomes from high stage compared to low stage patients. Furthermore, total and CD45(−) exosomes of high stage patients induced more apoptosis in CD8+ T cells than their low stage counterparts. CD69 suppression, a marker of reduced CD8+ T cell activation, was only mediated by CD45(−) exosomes. All fractions induced T_reg differentiation, defined by CD39 expression, but only CD45(−) exosomes showed a stage-dependent conversion. CD45(−) exosomes produced higher adenosine concentrations than CD45(+) exosomes, concluding that adenosine production measured in total exosomes mainly derives from TEX. The presented results show significant induction of immune suppression by TEX in HNSCC. This immunosuppressive effect supports the potential role of exosomes as liquid biomarkers for disease stage and level of immune suppression. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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15 pages, 1749 KiB

Open AccessArticle

Prognostic Significance of the Pluripotency Factors NANOG, SOX2, and OCT4 in Head and Neck Squamous Cell Carcinomas

by Daniel Pedregal-Mallo, Francisco Hermida-Prado, Rocío Granda-Díaz, Irene Montoro-Jiménez, Eva Allonca, Esperanza Pozo-Agundo, Mónica Álvarez-Fernández, César Álvarez-Marcos, Juana M. García-Pedrero and Juan Pablo Rodrigo

Cancers 2020, 12(7), 1794; https://doi.org/10.3390/cancers12071794 - 4 Jul 2020

Cited by 23 | Viewed by 3790

Abstract

Cancer stem cells (CSCs) play major roles in tumor initiation, progression, and resistance to cancer therapy. Several CSC markers have been studied in head and neck squamous cell carcinomas (HNSCC), including the pluripotency factors NANOG, SOX2, and OCT4; however, their clinical significance is [...] Read more.

Cancer stem cells (CSCs) play major roles in tumor initiation, progression, and resistance to cancer therapy. Several CSC markers have been studied in head and neck squamous cell carcinomas (HNSCC), including the pluripotency factors NANOG, SOX2, and OCT4; however, their clinical significance is still unclear. NANOG, SOX2, and OCT4 expression was evaluated by immunochemistry in 348 surgically-treated HNSCC, and correlated with clinicopathological parameters and patient outcomes. mRNA expression was further analyzed in 530 The Cancer Genome Atlas (TCGA) HNSCC. NANOG protein expression was detected in 250 (72%) cases, more frequently in patients with lymph node metastasis (p = 0.003), and was an independent predictor of better survival in multivariate analysis. While OCT4 expression was undetectable, SOX2 expression was observed in 105 (30%) cases, and strongly correlated with NANOG expression. Combined expression of both proteins showed the highest survival rates, and double-negative cases the worst survival. Strikingly, the impact of NANOG and SOX2 on outcome varied depending on tumor site and lymph node infiltration, specifically showing prognostic significance in pharyngeal tumors. Correlation between NANOG and SOX2 at mRNA and protein was specifically observed in node positive (N+) patients, and consistently correlated with better survival rates. According to our findings, NANOG protein expression is frequent in HNSCC, thereby emerging as an independent predictor of better prognosis in pharyngeal tumors. Moreover, this study uncovers a differential impact of NANOG and SOX2 expression on HNSCC prognosis, depending on tumor site and lymph node infiltration, which could facilitate high-risk patient stratification. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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18 pages, 266 KiB

Open AccessArticle

Outcomes for Elderly Patients Aged 70 to 80 Years or Older with Locally Advanced Oral Cavity Squamous Cell Carcinoma: A Propensity Score–Matched, Nationwide, Oldest Old Patient–Based Cohort Study

by Ben-Chang Shia, Lei Qin, Kuan-Chou Lin, Chih-Yuan Fang, Lo-Lin Tsai, Yi-Wei Kao and Szu-Yuan Wu

Cancers 2020, 12(2), 258; https://doi.org/10.3390/cancers12020258 - 21 Jan 2020

Cited by 19 | Viewed by 3033

Abstract

Purpose: Although clinicians encounter patients aged ≥70 years with locally advanced oral cavity squamous cell carcinoma (LA-OCSCC), no evidence is available to facilitate decision making regarding treatment for this elderly population. Methods: We selected elderly (≥70 years) patients from the Taiwan [...] Read more.

Purpose: Although clinicians encounter patients aged ≥70 years with locally advanced oral cavity squamous cell carcinoma (LA-OCSCC), no evidence is available to facilitate decision making regarding treatment for this elderly population. Methods: We selected elderly (≥70 years) patients from the Taiwan Cancer Registry database who had received a diagnosis of LA-OCSCC. Propensity score matching was performed. Cox proportional hazards model curves were used to analyze all-cause mortality in patients in different age groups receiving different treatments. Results: The matching process yielded a final cohort of 976 patients in concurrent chemoradiotherapy (CCRT), non-treatment, radiotherapy (RT) alone, and surgery cohorts who were eligible for further analysis. After stratified analysis, the adjusted hazard ratios (aHRs) (95% confidence intervals [CIs]) derived for surgery, RT alone, and non-treatment compared with CCRT were 0.66 (0.52 to 0.83), 1.02 (0.81 to 1.28), and 1.52 (1.21 to 1.91), respectively, in patients aged 70 to 80 years. In the oldest patients (aged >80 years), multivariate analysis indicated that the results of surgery or RT alone were nonsignificant compared with those of CCRT. The aHR (95% CI) derived for the highest mortality was 1.81 (1.11 to 2.40) for non-treatment compared with CCRT. Conclusions: Surgery for elderly patients with LA-OCSCC is associated with a significant survival benefit, but the association is nonsignificant in the oldest elderly patients. No survival differences were observed between RT alone and CCRT in these elderly patients. Non-treatment should not be an option for these patients. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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Open AccessReview

Paradigm Change in First-Line Treatment of Recurrent and/or Metastatic Head and Neck Squamous Cell Carcinoma

by Edith Borcoman, Gregoire Marret and Christophe Le Tourneau

Cancers 2021, 13(11), 2573; https://doi.org/10.3390/cancers13112573 - 24 May 2021

Cited by 16 | Viewed by 5643

Abstract

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) in combination with platinum-based chemotherapy has been for the decade standard of care for the treatment of head and neck squamous cell carcinomas (HNSCC) patients in the first-line recurrent and/or metastatic setting. [...] Read more.

Cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR) in combination with platinum-based chemotherapy has been for the decade standard of care for the treatment of head and neck squamous cell carcinomas (HNSCC) patients in the first-line recurrent and/or metastatic setting. The KEYNOTE-048 trial published last year established a new paradigm in this setting with the demonstration that immunotherapy should be given either alone or in combination with chemotherapy. Indeed, pembrolizumab, an antiprogrammed cell death 1 (PD-1) immune checkpoint inhibitor, improved overall survival as compared to the EXTREME regimen in patients expressing PD-L1 in the tumor microenvironment, which represents a large majority of the patient population. In this review, we will decipher this important change of paradigm in the first-line treatment of recurrent and/or metastatic HNSCC, and discuss associated challenges. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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15 pages, 4977 KiB

Open AccessEditor’s ChoiceReview

Recent Advances and Future Directions in Clinical Management of Head and Neck Squamous Cell Carcinoma

by Jameel Muzaffar, Shahla Bari, Kedar Kirtane and Christine H. Chung

Cancers 2021, 13(2), 338; https://doi.org/10.3390/cancers13020338 - 18 Jan 2021

Cited by 92 | Viewed by 7788

Abstract

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the head and neck region. The most common risk factors are smoking, excessive drinking, and human papillomavirus (HPV) infection. While the overall incidence of smoking is decreasing, the incidence [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) is the most common cancer arising in the head and neck region. The most common risk factors are smoking, excessive drinking, and human papillomavirus (HPV) infection. While the overall incidence of smoking is decreasing, the incidence of HPV-related HNSCC is increasing in the United States and Western Europe, which led to a shift in understanding of the pathophysiology, treatment, and prognosis of this disease. The outcomes for non-metastatic HNSCC remains very encouraging and continues to improve. Advances in radiation technology and techniques, better organ preserving surgical options, and multidisciplinary treatment modalities have improved cure rates for locally advanced HNSCC patients. The treatment of metastatic disease, however, remains an area of need. The advancement of immune checkpoint inhibitors has provided significantly better outcomes, but only a small proportion of patients obtain benefits. Most recurrent and/or metastatic HNSCC patients continue to have poor survival. This has led to the vigorous investigation of new biomarkers and biomarker-based therapies. Novel therapeutic options including adaptive cellular therapy and therapeutic vaccines are also on the horizon. In this review, we highlight the latest advances in the field of HNSCC and the future direction of research. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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19 pages, 312 KiB

Open AccessReview

Immunotherapy Breakthroughs in the Treatment of Recurrent or Metastatic Head and Neck Squamous Cell Carcinoma

by Christian Borel, Alain C. Jung and Mickaël Burgy

Cancers 2020, 12(9), 2691; https://doi.org/10.3390/cancers12092691 - 21 Sep 2020

Cited by 51 | Viewed by 5815

Abstract

Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no [...] Read more.

Head and neck squamous cell carcinoma (HNSCC) in the recurrent or metastatic (R/M) setting is a devastating disease with a poor prognosis. Until recently, the reference first line treatment was the EXTREME protocol, which yields a 10.1 months median survival, and almost no effective treatment are available in second line. Immune checkpoint inhibitors (ICIs) have changed the prognosis of several metastatic solid tumors. Given their inflammatory profile and high mutational burden, HNSCC is a good candidate for ICIs treatments. First, a strong pembrolizumab efficacy signal was shown in the Keynote-012 Phase Ib study. Then, the phase III Checkmate-141 study validated the efficacy of nivolumab in platinum-resistant patients. Finally, the first line conquest is acquired since the final results of the keynote-048 phase III study that demonstrated the superiority of pembrolizumab versus EXTREME in CPS ≥ 1 patients, and with the addition of platinum and 5FU in all patients. However, the first line treatment landscape is not frozen. Two studies (Checkmate-651 and Kestrel) are investigating the efficacy of the combination of antibodies raised against CTLA-4 and PD-(L)1. Results are impatiently awaited. Further progress needs the use of new immunotherapeutic agents such as monalizumab or ICOS agonist rather in combination with an anti-PD(L)1. New associations of ICIs and chemotherapeutic or targeted therapeutic agents are also actively investigated. Finally, ICIs has to be studied in the locally advanced setting where there is a chance of cure. Several trials are testing the potential synergistic combination of ICIs with radiotherapy and platinum or cetuximab, or ICIs used in a neoadjuvant setting. Full article

(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma (HNSCC))

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