Head and neck squamous cell carcinomas (HNSCCs) are a type of common malignant tumor, mainly manifesting as oropharyngeal, oral cavity, laryngopharyngeal, hypopharyngeal, and laryngeal cancers. These highly aggressive malignant tumors reportedly affect more than 830,000 patients worldwide annually. Currently, the main treatments for HNSCC include surgery, radiotherapy, chemotherapy, immunotherapy, and combination therapy. However, the overall 5-year survival rate of HNSCC has remained 50%, and it has not significantly improved in the past 10 years.

A significant subset of head and neck cancers display a T-cell inflamed phenotype, suggesting that patients with these tumors should respond to therapeutic approaches to strengthen anti-tumor immune responses. A significant barrier to developing an effective anti-tumor immune response, at baseline or in response to immunotherapy, is the development of an immunosuppressive tumor microenvironment (TME). Previous studies have shown that TME plays a crucial role in the recurrence, metastasis, and drug resistance of patients with HNSCC.

While progress to date has been encouraging, critical scientific gaps exist regarding our understanding of the relationship between immune system control during the maintenance of oral health and disease pathogenesis. Recent advances in immunotherapy for HNSCCs have led to the implementation of anti-programmed death receptor 1 (PD-1) immunotherapy as the standard of care for recurrent/metastatic HNSCC. However, most tumors do not respond to these therapies, indicating that these tumors are not immunogenic or that other immunosuppressive mechanisms might be at play. Moreover, mechanisms underlying gender-based, age-related differences in immune reactivity, recurrence-related oral sequelae, and treatment options are yet to be understood. Inflammation-driven phenotypic plasticity and its effects on the immune landscape of chronic oral inflammation and tumor development, progression, and metastasis are relatively unknown. Understanding the plasticity of tissue-resident and hematopoietic immune sentinels enriched at the oral mucosal surfaces and their crosstalk with the microenvironment will shed light on the mechanisms of persistence and immune memory in the oral cavity. Specifically, how these tissue-specific cues participate in the training of immune responsiveness in the oral cavity and the mechanisms mediating homeostatic immunity at this interface remain to be defined.

Several well-described effector immune cell suppression mechanisms in the HNSCC TME are known players. However, more insights are needed from current trials designed to translate what we have learned from pre-clinical and correlative clinical studies into improved responses in patients following immune-activating therapies. These and other critical developments are necessary to 1) advance knowledge of immune training, immune memory, and homeostatic immunity in TME, and 2) further develop and adapt novel tools and technologies for precise modulation of immune system plasticity to restore normal homeostasis of dental, oral and craniofacial tissues.

We welcome original research, reviews, mini-reviews, opinions, hypotheses, and case reports that cover basic and clinical research covering but not limited to, the following topics:

• The role of anti-tumor and pro-tumor immune cells and extracellular components in the TME of HNSCC

• Crosstalk between tumor and immune system to modulate their respective adaptive functions in the context of inflammatory stimuli and disease pathogenesis

• Outline growth factors/cytokines/molecules in the TME known to regulate immunosuppressive cells

• The role and underlying mechanism of radiation therapy on the TME, immune cells, and immune response

• Tissue-resident and recruited immune cells interactions with tumor cells

• The interactions between innate and adaptive immune systems regulate gene regulatory networks in a cell-environment- and time-dependent manner in dental, oral, and craniofacial tissues

• The importance of immunological memory and the interactions between innate and adaptive immunity

• Elucidating how microbial-derived metabolites influence oral tissues in the context of HNSCC-associated chronic inflammation and manipulating TME

• Investigating mechanisms of cellular metabolism in immune cells and non-immune cells regulate trained memory and oral immune tolerance

• Interrogating how changes in transcriptional programming and epigenetic rewiring lead to downstream effects of immune memory at the oral mucosal barrier

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Frontiers in Oral Health

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