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Cancers
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Advances in Head and Neck Squamous Cell Carcinoma
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Advances in Head and Neck Squamous Cell Carcinoma

A special issue of Cancers (ISSN 2072-6694). This special issue belongs to the section "Cancer Therapy".

Deadline for manuscript submissions: closed (1 March 2024) | Viewed by 12863

Special Issue Editors

Prof. Dr. Patrick Ha

E-Mail Website
Guest Editor
Department of Otolaryngology—Head and Neck Surgery, University of California San Francisco, San Francisco, CA, USA
Interests: salivary gland tumors; signaling pathways; gene fusions; promoter methylation; genome-wide analysis; clinical trials
Special Issues, Collections and Topics in MDPI journals
Dr. Sidharth V. Puram

E-Mail Website
Guest Editor
1. Department of Otolaryngology-Head and Neck Surgery, Washington University School of Medicine, 4921 Parkview Pl, St. Louis, MO 63110, USA
2. Department of Genetics, Washington University School of Medicine, 4921 Parkview Pl, St. Louis, MO 63110, USA
Interests: intra-tumoral heterogeneity; head and neck cancer; metastasis; treatment resistance; epigenetic and transcriptional regulation
Special Issues, Collections and Topics in MDPI journals
Dr. Nicole C. Schmitt

E-Mail Website
Guest Editor
1. Department of Otolaryngology-Head and Neck Surgery, Emory University School of Medicine, Atlanta, GA 30332, USA
2. Winship Cancer Institute, Emory University School of Medicine, Atlanta, GA 30332, USA
Interests: immune effects of novel therapeutic combinations for head and neck cancer

Special Issue Information

Dear Colleagues,

It is an exciting time in the field of head and neck cancer. Numerous advances in robotic surgery, radiation therapy techniques, novel medical therapies, and biomarker diagnostics have altered the treatment of patients. Now, more than ever, it is important to keep abreast of new findings and to determine how to best incorporate new data into practice. I hope that this edition will be representative of these discoveries and demonstrate the breadth of ongoing research in these domains.

Prof. Dr. Patrick Ha
Dr. Sidharth V. Puram
Dr. Nicole C. Schmitt
Guest Editors

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Cancers is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 2900 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • head and neck cancer
  • biomarkers
  • surgery
  • radiation
  • chemotherapy
  • immunotherapy
  • targeted

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Published Papers (6 papers)

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Research

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20 pages, 543 KiB  
Article
Impact of Nutritional Status of Patients with Head and Neck Squamous Cell Carcinoma on the Expression Profile of Ghrelin, Irisin, and Titin
by Agata Andruszko, Jarosław Szydłowski, Beniamin Oskar Grabarek, Katarzyna Mazur, Tomasz Sirek, Piotr Ossowski, Mieszko Kozikowski, Konrad Kaminiów, Ariadna Zybek-Kocik and Jacek Banaszewski
Cancers 2024, 16(2), 437; https://doi.org/10.3390/cancers16020437 - 19 Jan 2024
Viewed by 1674
Abstract
The goal of this paper was the evaluation of the changes in the expression profile of irisin, ghrelin, and titin in the carcinoma tissue and in the blood of patients with head and neck squamous cell carcinoma (HNSCC), including determining the profile of [...] Read more.
The goal of this paper was the evaluation of the changes in the expression profile of irisin, ghrelin, and titin in the carcinoma tissue and in the blood of patients with head and neck squamous cell carcinoma (HNSCC), including determining the profile of their expression in relation to patient nutrition. The study included 56 patients with diagnosed squamous cell carcinoma of HNSCC in the T3 and T4 stages of the disease. Healthy control tissue specimens were collected from an area 10 mm outside the histologically negative margin. In turn, the blood and serum from the control group came from healthy volunteers treated for non-oncologic reasons (n = 70). The molecular analysis allowed us to determine the profile of irisin, ghrelin, and titin methylation, evaluate their expression on the level of mRNA (quantitative Reverse Transcription Polymerase Chain Reaction; qRT-PCR) and protein (Enzyme-Linked Immunosorbent Assay Reaction; ELISA) in the carcinoma tissue and the margin of healthy tissue, as well as in serum of patients in the study and control groups. At the start of our observations, a Body Mass Index (BMI) < 18.5 was noted in 42 of the patients, while six months after the treatment a BMI < 18.5 was noted in 29 patients. We also noted a decrease in the expression of irisin, ghrelin, and titin both on the level of mRNA and protein, as well as a potential regulation of their expression via DNA methylation. There is no convincing evidence that the proteins assayed in the present work are specific with regard to HNSSC. Full article
(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma)
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11 pages, 2033 KiB  
Article
Validation of a Machine Learning Model to Predict Immunotherapy Response in Head and Neck Squamous Cell Carcinoma
by Andrew Sangho Lee, Cristina Valero, Seong-keun Yoo, Joris L. Vos, Diego Chowell and Luc G. T. Morris
Cancers 2024, 16(1), 175; https://doi.org/10.3390/cancers16010175 - 29 Dec 2023
Viewed by 1734
Abstract
Head and neck squamous-cell carcinoma (HNSCC) is a disease with a generally poor prognosis; half of treated patients eventually develop recurrent and/or metastatic (R/M) disease. Patients with R/M HNSCC generally have incurable disease with a median survival of 10 to 15 months. Although [...] Read more.
Head and neck squamous-cell carcinoma (HNSCC) is a disease with a generally poor prognosis; half of treated patients eventually develop recurrent and/or metastatic (R/M) disease. Patients with R/M HNSCC generally have incurable disease with a median survival of 10 to 15 months. Although immune-checkpoint blockade (ICB) has improved outcomes in patients with R/M HNSCC, identifying patients who are likely to benefit from ICB remains a challenge. Biomarkers in current clinical use include tumor mutational burden and immunohistochemistry for programmed death-ligand 1, both of which have only modest predictive power. Machine learning (ML) has the potential to aid in clinical decision-making as an approach to estimate a tumor’s likelihood of response or a patient’s likelihood of experiencing clinical benefit from therapies such as ICB. Previously, we described a random forest ML model that had value in predicting ICB response using 11 or 16 clinical, laboratory, and genomic features in a pan-cancer development cohort. However, its applicability to certain cancer types, such as HNSCC, has been unknown, due to a lack of cancer-type-specific validation. Here, we present the first validation of a random forest ML tool to predict the likelihood of ICB response in patients with R/M HNSCC. The tool had adequate predictive power for tumor response (area under the receiver operating characteristic curve = 0.65) and was able to stratify patients by overall (HR = 0.53 [95% CI 0.29–0.99], p = 0.045) and progression-free (HR = 0.49 [95% CI 0.27–0.87], p = 0.016) survival. The overall accuracy was 0.72. Our study validates an ML predictor in HNSCC, demonstrating promising performance in a novel cohort of patients. Further studies are needed to validate the generalizability of this algorithm in larger patient samples from additional multi-institutional contexts. Full article
(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma)
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9 pages, 1095 KiB  
Article
Immune Cell Deconvolution Reveals Possible Association of γδ T Cells with Poor Survival in Head and Neck Squamous Cell Carcinoma
by Anuraag S. Parikh, Yize Li, Angela Mazul, Victoria X. Yu, Wade Thorstad, Jason Rich, Randal C. Paniello, Salvatore M. Caruana, Scott H. Troob, Ryan S. Jackson, Patrik Pipkorn, Paul Zolkind, Zongtai Qi, Douglas Adkins, Li Ding and Sidharth V. Puram
Cancers 2023, 15(19), 4855; https://doi.org/10.3390/cancers15194855 - 5 Oct 2023
Cited by 2 | Viewed by 2128
Abstract
(1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and [...] Read more.
(1) Background: The role of rare immune cell subtypes in many solid tumors, chief among them head and neck squamous cell carcinoma (HNSCC), has not been well defined. The objective of this study was to assess the association between proportions of common and rare immune cell subtypes and survival outcomes in HNSCC. (2) Methods: In this cohort study, we utilized a deconvolution approach based on the CIBERSORT algorithm and the LM22 signature matrix to infer proportions of immune cell subtypes from 517 patients with untreated HPV-negative HNSCC from The Cancer Genome Atlas. We performed univariate and multivariable survival analysis, integrating immune cell proportions with clinical, pathologic, and genomic data. (3) Results: We reliably deconvolved 22 immune cell subtypes in most patients and found that the most common immune cell types were M0 macrophages, M2 macrophages, and memory resting CD4 T cells. In the multivariable analysis, we identified advanced N stage and the presence of γδ T cells as independently predictive of poorer survival. (4) Conclusions: We uncovered that γδ T cells in the tumor microenvironment were a negative predictor of survival among patients with untreated HNSCC. Our findings underscore the need to better understand the role of γδ T cells in HNSCC, including potential pro-tumorigenic mechanisms, and whether their presence may predict the need for alternative therapy approaches. Full article
(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma)
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25 pages, 3899 KiB  
Article
A Network Landscape of HPVOPC Reveals Methylation Alterations as Significant Drivers of Gene Expression via an Immune-Mediated GPCR Signal
by Jesse R. Qualliotine, Takuya Nakagawa, Sara Brin Rosenthal, Sayed Sadat, Carmen Ballesteros-Merino, Guorong Xu, Adam Mark, Art Nasamran, J. Silvio Gutkind, Kathleen M. Fisch, Theresa Guo, Bernard A. Fox, Zubair Khan, Alfredo A. Molinolo and Joseph A. Califano
Cancers 2023, 15(17), 4379; https://doi.org/10.3390/cancers15174379 - 1 Sep 2023
Cited by 2 | Viewed by 2039
Abstract
HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this [...] Read more.
HPV-associated oropharynx carcinoma (HPVOPC) tumors have a relatively low mutational burden. Elucidating the relative contributions of other tumor alterations, such as DNA methylation alterations, alternative splicing events (ASE), and copy number variation (CNV), could provide a deeper understanding of carcinogenesis drivers in this disease. We applied network propagation analysis to multiple classes of tumor alterations in a discovery cohort of 46 primary HPVOPC tumors and 25 cancer-unaffected controls and validated our findings with TCGA data. We identified significant overlap between differential gene expression networks and all alteration classes, and this association was highest for methylation and lowest for CNV. Significant overlap was seen for gene clusters of G protein-coupled receptor (GPCR) pathways. HPV16–human protein interaction analysis identified an enriched cluster defined by an immune-mediated GPCR signal, including CXCR3 cytokines CXCL9, CXCL10, and CXCL11. CXCR3 was found to be expressed in primary HPVOPC, and scRNA-seq analysis demonstrated CXCR3 ligands to be highly expressed in M2 macrophages. In vivo models demonstrated decreased tumor growth with antagonism of the CXCR3 receptor in immunodeficient but not immunocompetent mice, suggesting that the CXCR3 axis can drive tumor proliferation in an autocrine fashion, but the effect is tempered by an intact immune system. In conclusion, methylation, ASE, and SNV alterations are highly associated with network gene expression changes in HPVOPC, suggesting that ASE and methylation alterations have an important role in driving the oncogenic phenotype. Network analysis identifies GPCR networks, specifically the CXCR3 chemokine axis, as modulators of tumor–immune interactions that may have proliferative effects on primary tumors as well as a role for immunosurveillance; however, CXCR3 inhibition should be used with caution, as these agents may both inhibit and stimulate tumor growth considering the competing effects of this cytokine axis. Further investigation is needed to explore opportunities for targeted therapy in this setting. Full article
(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma)
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18 pages, 2006 KiB  
Article
CDK4/6 Inhibition Induces Senescence and Enhances Radiation Response by Disabling DNA Damage Repair in Oral Cavity Squamous Cell Carcinoma
by Nitisha Shrivastava, Claudia Gutierrez Chavez, Daniel Li, Vikas Mehta, Carlos Thomas, Cory D. Fulcher, Nicole Kawachi, Danielle M. Bottalico, Michael B. Prystowsky, Indranil Basu, Chandan Guha and Thomas J. Ow
Cancers 2023, 15(7), 2005; https://doi.org/10.3390/cancers15072005 - 28 Mar 2023
Cited by 9 | Viewed by 2793
Abstract
Purpose: HPV(−) OCSCC resists radiation treatment. The CDKN2A gene, encoding p16INK4A, is commonly disrupted in OCSCC. p16 inhibits CDK4/CDK6, leading to cell cycle arrest, but the biological sequelae of CDK4/6 inhibition in OCSCC remains understudied. This study examines whether inhibition of CDK4/6 enhances [...] Read more.
Purpose: HPV(−) OCSCC resists radiation treatment. The CDKN2A gene, encoding p16INK4A, is commonly disrupted in OCSCC. p16 inhibits CDK4/CDK6, leading to cell cycle arrest, but the biological sequelae of CDK4/6 inhibition in OCSCC remains understudied. This study examines whether inhibition of CDK4/6 enhances radiation response in OCSCC. Methods: MTT assays were performed in OCSCC cell lines HN5 and CAL27 following treatment with palbociclib. Clonogenic survival and synergy were analyzed after radiation (RT-2 or 4Gy), palbociclib (P) (0.5 µM or 1 µM), or concurrent combination treatment (P+RT). DNA damage/repair and senescence were examined. CDK4/6 were targeted via siRNA to corroborate P+RT effects. Three-dimensional immortalized spheroids and organoids derived from patient tumors (conditionally reprogrammed OCSCC CR-06 and CR-18) were established to further examine and validate responses to P+RT. Results: P+RT demonstrated reduced viability and synergy, increased β-gal expression (~95%), and ~two-fold higher γH2AX. Rad51 and Ku80 were reduced after P+RT, indicating impairment of both HR and NHEJ. siCDK4/6 increased senescence with radiation. Spheroids showed reduced proliferation and size with P+RT. CR-06 and CR-18 further demonstrated three-fold reduced proliferation and organoids size with P+RT. Conclusion: Targeting CDK4/6 can lead to improved efficacy when combined with radiation in OCSCC by inducing senescence and inhibiting DNA damage repair. Full article
(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma)
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Review

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19 pages, 1685 KiB  
Review
Experimental Modeling of Host–Bacterial Interactions in Head and Neck Squamous Cell Carcinoma
by Ogoegbunam Okolo, Emily Honzel, William R. Britton, Victoria X. Yu, Samuel Flashner, Cecilia Martin, Hiroshi Nakagawa and Anuraag S. Parikh
Cancers 2023, 15(24), 5810; https://doi.org/10.3390/cancers15245810 - 12 Dec 2023
Viewed by 1710
Abstract
The microscopic species colonizing the human body, collectively referred to as the microbiome, play a crucial role in the maintenance of tissue homeostasis, immunity, and the development of disease. There is evidence to suggest associations between alterations in the microbiome and the development [...] Read more.
The microscopic species colonizing the human body, collectively referred to as the microbiome, play a crucial role in the maintenance of tissue homeostasis, immunity, and the development of disease. There is evidence to suggest associations between alterations in the microbiome and the development of head and neck squamous cell carcinomas (HNSCC). The use of two-dimensional (2D) modeling systems has made significant strides in uncovering the role of microbes in carcinogenesis; however, direct mechanistic links remain in their infancy. Patient-derived three-dimensional (3D) HNSCC organoid and organotypic models have recently been described. Compared to 2D models, 3D organoid culture systems effectively capture the genetic and epigenetic features of parent tissue in a patient-specific manner and may offer a more nuanced understanding of the role of host–microbe responses in carcinogenesis. This review provides a topical literature review assessing the current state of the field investigating the role of the microbiome in HNSCC; including in vivo and in vitro modeling methods that may be used to characterize microbiome–epithelial interactions. Full article
(This article belongs to the Special Issue Advances in Head and Neck Squamous Cell Carcinoma)
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