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Cancers
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Tumor Microenvironment of Head and Neck Cancer
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Tumor Microenvironment of Head and Neck Cancer

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

Deadline for manuscript submissions: closed (31 March 2022) | Viewed by 11371

Special Issue Editor

Dr. Steve Oghumu

E-Mail Website
Guest Editor
Department of Pathology, College of Medicine, Ohio State University, 337 Hamilton Hall, 1645 Neil Ave, Columbus, OH 43210, USA
Interests: immunology; mechanisms of infectious and neoplastic disease; chemoprevention
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear colleagues,

Head and neck cancer poses a significant public health problem worldwide. It is a heterogenous disease, affecting various anatomic sites, with distinct etiologies, risk factors, and prognoses. Current research demonstrates that the head and neck cancer tumor microenvironment (TME) plays a major role in determining disease outcome and response to therapy. While there is much that has been learned on how tumor cells create an immunosuppressive TME, there are still many unknowns on the interactions between the components of the TME and how they can inform prognoses and treatment strategies in head and neck cancer.

The TME comprises cellular (stromal cells, immune cells, fibroblasts, cancer stem cells) and non-cellular (cytokines, growth factors, angiogenic factors, extracellular matrix) components. Immune cells in the head and neck cancer TME that affect tumor growth and metastasis include cells of myeloid origin such as myeloid derived suppressor cells (MDSCs), tumor-associated macrophages (TAMs), dendritic cells, and cells of lymphoid origin such as regulatory T cells (Tregs), cytotoxic T lymphocytes (CTLs), and natural killer (NK) cells. MDSCs, TAMs, and Tregs promote immunosuppression and tumor immune escape. These cells also interact with non-immune cells and noncellular components of the TME to create a dynamic environment that ultimately determines head and neck cancer outcomes and treatment responses.

Immunotherapeutic drugs which target immune cells in the TME are used in routine head and neck cancer treatment, but despite their success, only a few patients respond to them. This Special Issue will highlight the complex interactions of cells in the TME of head and neck cancer, identify novel approaches to head and neck cancer prevention and treatment, and provide insights on strategies to improve patient responses by modifying the head and neck cancer TME.

Dr. Steve Oghumu
Guest Editor

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 short 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.

Published Papers (5 papers)

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Research

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15 pages, 2605 KiB  
Article
Ionizing Radiation Reduces Head and Neck Squamous Cell Carcinoma Cell Viability and Is Associated with Predictive Tumor-Specific T Cell Responses
by Puja Upadhaya, Nathan Ryan, Peyton Roth, Travis Pero, Felipe Lamenza, Anna Springer, Pete Jordanides, Hasan Pracha, Darrion Mitchell and Steve Oghumu
Cancers 2023, 15(13), 3334; https://doi.org/10.3390/cancers15133334 - 25 Jun 2023
Viewed by 1315
Abstract
Head and neck squamous cell carcinoma (HNSCC) is common and deadly, and there is a need for improved strategies to predict treatment responses. Ionizing radiation (IR) has been demonstrated to improve HNSCC outcomes, but its effects on immune responses are not well characterized. [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) is common and deadly, and there is a need for improved strategies to predict treatment responses. Ionizing radiation (IR) has been demonstrated to improve HNSCC outcomes, but its effects on immune responses are not well characterized. We determined the impact of IR on T cell immune responses ex vivo. Human and mouse HNSCC cells were exposed to IR ranging from 20 to 200 Gy to determine cell viability and the ability to stimulate T-cell-specific responses. Lymph node cells of LY2 and MOC2 tumor-bearing or non-tumor-bearing mice were re-stimulated with a tumor antigen derived from LY2 or MOC2 cells treated with 200 Gy IR, ultraviolet (UV) exposure, or freeze/thaw cycle treatments. T cell proliferation and cytokine production were compared to T cells restimulated with plate-bound CD3 and CD28 antibodies. Human and mouse HNSCC cells showed reduced viability in response to ionizing radiation in a dose-dependent manner, and induced expression of T cell chemotactic cytokines. Tumor antigens derived from IR-treated LY2 and MOC2 cells induced greater proliferation of lymph node cells from tumor-bearing mice and induced unique T cell cytokine expression profiles. Our results demonstrate that IR induces potent tumoral immune responses, and IR-generated tumor antigens can potentially serve as an indicator of antitumor immune responses to HNSCC in ex vivo T cell restimulation assays. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Head and Neck Cancer)
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14 pages, 1830 KiB  
Article
Targeting the Tumor Microenvironment through mTOR Inhibition and Chemotherapy as Induction Therapy for Locally Advanced Head and Neck Squamous Cell Carcinoma: The CAPRA Study
by Diane Evrard, Clément Dumont, Michel Gatineau, Jean-Pierre Delord, Jérôme Fayette, Chantal Dreyer, Annemilaï Tijeras-Raballand, Armand de Gramont, Jean-François Delattre, Muriel Granier, Nasredine Aissat, Marie-Line Garcia-Larnicol, Khemaies Slimane, Benoist Chibaudel, Eric Raymond, Christophe Le Tourneau and Sandrine Faivre
Cancers 2022, 14(18), 4509; https://doi.org/10.3390/cancers14184509 - 17 Sep 2022
Cited by 4 | Viewed by 1733
Abstract
Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study [...] Read more.
Mammalian target of rapamycin (mTOR) regulates cellular functions by integrating intracellular signals and signals from the tumor microenvironment (TME). The PI3K-AKT-mTOR pathway is activated in 70% of head and neck squamous cell carcinoma (HNSCC) and associated with poor prognosis. This phase I-II study investigated the effect of mTOR inhibition using weekly everolimus (30 mg for dose level 1, 50 mg for dose level 2) combined with weekly induction chemotherapy (AUC2 carboplatin and 60 mg/m2 paclitaxel) in treatment-naïve patients with locally advanced T3-4/N0-3 HNSCC. Patients received 9 weekly cycles before chemoradiotherapy. Objectives were safety and antitumor activity along with tissue and blood molecular biomarkers. A total of 50 patients were enrolled. Among 41 evaluable patients treated at the recommended dose of 50 mg everolimus weekly, tolerance was good and overall response rate was 75.6%, including 20 major responses (≥50% reduction in tumor size). A significant decrease in expression of p-S6K (p-value: 0.007) and Ki67 (p-value: 0.01) was observed in post-treatment tumor tissue. Pro-immunogenic cytokine release (Th1 cytokines IFN-γ, IL-2, and TNF-β) was observed in the peripheral blood. The combination of everolimus and chemotherapy in HNSCC was safe and achieved major tumor responses. This strategy favorably impacts the TME and might be combined with immunotherapeutic agents. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Head and Neck Cancer)
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21 pages, 2982 KiB  
Article
mRNA Subtype of Cancer-Associated Fibroblasts Significantly Affects Key Characteristics of Head and Neck Cancer Cells
by Barbora Peltanová, Hana Holcová Polanská, Martina Raudenská, Jan Balvan, Jiří Navrátil, Tomáš Vičar, Jaromír Gumulec, Barbora Čechová, Martin Kräter, Jochen Guck, David Kalfeřt, Marek Grega, Jan Plzák, Jan Betka and Michal Masařík
Cancers 2022, 14(9), 2286; https://doi.org/10.3390/cancers14092286 - 03 May 2022
Cited by 3 | Viewed by 2520
Abstract
Head and neck squamous cell carcinomas (HNSCC) belong among severe and highly complex malignant diseases showing a high level of heterogeneity and consequently also a variance in therapeutic response, regardless of clinical stage. Our study implies that the progression of HNSCC may be [...] Read more.
Head and neck squamous cell carcinomas (HNSCC) belong among severe and highly complex malignant diseases showing a high level of heterogeneity and consequently also a variance in therapeutic response, regardless of clinical stage. Our study implies that the progression of HNSCC may be supported by cancer-associated fibroblasts (CAFs) in the tumour microenvironment (TME) and the heterogeneity of this disease may lie in the level of cooperation between CAFs and epithelial cancer cells, as communication between CAFs and epithelial cancer cells seems to be a key factor for the sustained growth of the tumour mass. In this study, we investigated how CAFs derived from tumours of different mRNA subtypes influence the proliferation of cancer cells and their metabolic and biomechanical reprogramming. We also investigated the clinicopathological significance of the expression of these metabolism-related genes in tissue samples of HNSCC patients to identify a possible gene signature typical for HNSCC progression. We found that the right kind of cooperation between cancer cells and CAFs is needed for tumour growth and progression, and only specific mRNA subtypes can support the growth of primary cancer cells or metastases. Specifically, during coculture, cancer cell colony supporting effect and effect of CAFs on cell stiffness of cancer cells are driven by the mRNA subtype of the tumour from which the CAFs are derived. The degree of colony-forming support is reflected in cancer cell glycolysis levels and lactate shuttle-related transporters. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Head and Neck Cancer)
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15 pages, 3342 KiB  
Article
Prognostic Matrisomal Gene Panel and Its Association with Immune Cell Infiltration in Head and Neck Carcinomas
by Yuri Belotti, Su Bin Lim, Narayanan Gopalakrishna Iyer, Wan-Teck Lim and Chwee Teck Lim
Cancers 2021, 13(22), 5761; https://doi.org/10.3390/cancers13225761 - 17 Nov 2021
Cited by 4 | Viewed by 2547
Abstract
Squamous cell carcinoma of the head and neck (SCCHN) is common worldwide and related to several risk factors including smoking, alcohol consumption, poor dentition and human papillomavirus (HPV) infection. Different etiological factors may influence the tumor microenvironment and play a role in dictating [...] Read more.
Squamous cell carcinoma of the head and neck (SCCHN) is common worldwide and related to several risk factors including smoking, alcohol consumption, poor dentition and human papillomavirus (HPV) infection. Different etiological factors may influence the tumor microenvironment and play a role in dictating response to therapeutics. Here, we sought to investigate whether an early-stage SCCHN-specific prognostic matrisome-derived gene signature could be identified for HPV-negative SCCHN patients (n = 168), by applying a bioinformatics pipeline to the publicly available SCCHN-TCGA dataset. We identified six matrisome-derived genes with high association with prognostic outcomes in SCCHN. A six-gene risk score, the SCCHN TMI (SCCHN-tumor matrisome index: composed of MASP1, EGFL6, SFRP5, SPP1, MMP8 and P4HA1) was constructed and used to stratify patients into risk groups. Using machine learning-based deconvolution methods, we found that the risk groups were characterized by a differing abundance of infiltrating immune cells. This work highlights the key role of immune infiltration cells in the overall survival of patients affected by HPV-negative SCCHN. The identified SCCHN TMI represents a genomic tool that could potentially aid patient stratification and selection for therapy in these patients. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Head and Neck Cancer)
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Review

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13 pages, 891 KiB  
Review
The Hidden Link of Exosomes to Head and Neck Cancer
by Yong Teng, Lixia Gao, Reid Loveless, Juan P. Rodrigo, Primož Strojan, Stefan M. Willems, Cherie-Ann Nathan, Antti A. Mäkitie, Nabil F. Saba and Alfio Ferlito
Cancers 2021, 13(22), 5802; https://doi.org/10.3390/cancers13225802 - 19 Nov 2021
Cited by 12 | Viewed by 2580
Abstract
Head and neck squamous cell carcinoma (HNSCC) represents an aggressive and heterogenous group of cancers whose pathologies remain largely unresolved. Despite recent advances in HNSCC therapeutic strategies, the overall survival of HNSCC patients remains poor and continues to prompt efforts to develop more [...] Read more.
Head and neck squamous cell carcinoma (HNSCC) represents an aggressive and heterogenous group of cancers whose pathologies remain largely unresolved. Despite recent advances in HNSCC therapeutic strategies, the overall survival of HNSCC patients remains poor and continues to prompt efforts to develop more effective therapies. Exosomes are a subtype of extracellular vesicles secreted by a variety of cells that have begun to spark significant interest in their roles in cancer. As membranous vesicles, spanning from 30–150 nm in diameter, exosomes mediate the transport of various molecules, such as proteins, nucleic acids, and lipids, intercellularly throughout the body. In doing so, exosomes not only act to deliver materials to cancer cells but also as signals that can confer their progression. Accumulating evidence shows the direct correlation between exosomes and the aggressiveness of HNSCC. However, more research is warranted in this field to further our understanding. In this review, we attempt to highlight the tumor-supporting roles and therapeutic potential of exosomes in HNSCC. We introduce first the biogenesis and component features of exosomes, followed by their involvement in HNSCC proliferation and metastasis. We then move on to discuss HNSCC-derived exosomes’ influence on the tumor microenvironment and their function in tumor drug resistance. Finally, we explore the promising potential of exosomes as HNSCC biomarkers and therapeutic targets and drug carriers for HNSCC treatments. Full article
(This article belongs to the Special Issue Tumor Microenvironment of Head and Neck Cancer)
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