[Comparison of T cell response in the tumor milieu of patients with HPV+ and HPV- head and neck cancer]. / Vergleich der T-Zell-Antwort im Tumormilieu von Patienten mit HPV+- und HPV−-Kopf-Hals-Karzinom.

BACKGROUND: The incidence of HPV-associated squamous cell carcinoma of the head and neck region (HNSCC) has increased dramatically in recent years. Despite a similar localization (oropharyngeal squamous cell epithelia) to smoking- and alcohol-associated cancers, HPV-associated carcinomas are considered to represent a distinct entity. Reasons for the different therapeutic responses of the two tumor entities are not yet fully understood. METHODS AND OBJECTIVE: This review investigates the importance of tumor-infiltrating lymphocytes in HPV+ and HPV- HNSCC by means of articles and publications concerning the tumor micromilieu, effects on prognosis, and patients' therapeutic responses. RESULTS: HNSCC patients with a positive HPV status and increased frequencies of CD8+ T cells (CD, cluster of differentiation) demonstrated an improved therapeutic response and improved outcomes. Decreased expression of the EGF (epidermal growth factor) receptor correlates with increased TH1 cytokine secretion by CD4+ T cells, which, in their role as T helper cells, can activate macrophages, dendritic cells, and cytotoxic T cells, amongst others. Regulatory T cells (Treg) execute an immune-suppressive effect in the tumor micromilieu through different metabolic and signaling pathways (IL[interleukin]­4, IL-10, TGF­ß ["transforming growth factor­ß"]). CONCLUSION: The importance of the adaptive immune response for treatment response and patients' prognosis has been supported by different investigations. Understanding the immunological processes in the tumor environment plays an important role for the development of new treatment approaches.

[Stimulatory and inhibitory signaling pathways of the T cell-APC interaction and the effect of TLR agonists on APCs]. / Stimulierende und inhibierende Signalwege der APZ- und T-Zell-Interaktion sowie Einfluss von TLR-Agonisten auf APZ.

BACKGROUND: CD8+ cells are key players in the identification and elimination of cancer cells. Cancers can escape an effective T cell response by inducing an exhausted cell state, which limits the cytotoxic capacity of the effector cells. Among other mechanisms, new checkpoint inhibitors reactivate exhausted, dysfunctional T cells. CD8+ T cells can eliminate tumor cells after presentation of tumor-specific antigens via antigen-presenting cells (APCs). APC-mediated tumor recognition is mainly stimulated by Toll-like receptors (TLRs). OBJECTIVE: This study investigates the effect of TLR agonists on APCs as well as stimulatory and inhibitory signaling pathways of the T cell-APC interaction. MATERIALS AND METHODS: Gene expression of interleukin (IL)12 and programmed death ligand 1 (PD-L1) was analyzed by quantitative polymerase chain reaction (qPCR) after 0, 8, 24, and 48 h of CD14+ cell stimulation with CpG. Protein expression of inhibitor of nuclear factor kappa B (IκBα) after CpG stimulation was investigated by western blot. CD8+ T cells were stimulated for 72 h with or without programmed cell death protein 1 (PD-1) checkpoint blockade and analyzed for expression of PD­1, Tim­3, CTLA4, and Lag3 by flow cytometry. RESULTS: TLR stimulation (by unmethylated CpG DNA) of APCs upregulates immunostimulatory signals such as IL12 expression but also activates immunoinhibitory signaling pathways such as PD-L1 expression. This signaling is NF-κB dependent. After blockade of the PD-1/PD-L1 signaling pathway, overexpression of other immune checkpoint inhibitory receptors was observed-a potential explanation for lacking therapeutic responses after TLR stimulation with PD­1 checkpoint blockade. CONCLUSION: TLR stimulation causes APCs in the tumor microenvironment to upregulate PD-L1 in an NF-κB-mediated fashion, thereby contributing to CD8+ T cell exhaustion. The effect of PD­1 blockade after TLR stimulation might be impaired due to upregulation of other checkpoint inhibitors.

[Tumor microenvironment in salivary gland carcinomas: Consequences for new therapeutic concepts]. / Das Tumormikromilieu bei Speicheldrüsenkarzinomen ­ mögliche Konsequenzen für neue Therapiekonzepte.

INTRODUCTION: Salivary gland carcinomas (SGCs) are rare tumors which represent a challenge for diagnosis and therapy due to their histological diversity and the different disease courses depending on the respective subtype. Little is known about the composition of the tumor microenvironment in SGCs. A more comprehensive understanding of the relevant molecular changes and immunological processes of the tumor and surrounding stroma could help to improve therapeutic efficiency, for example by adjuvant immunomodulation. METHODS: This manuscript highlights recent studies analyzing the composition of the tumor microenvironment in salivary gland carcinomas. RESULTS: The tumor microenvironment displays a significant diversity in the composition of immune cells among different tumor entities. In one third of the SGCs, an expression of cell surface molecule LAG3 on tumor infiltrating lymphocytes could be observed. LAG3-similar to CTLA­4 and PD-1-inhibits cellular proliferation, activation, and homeostasis of antitumor-effective T cells. Especially, prognostically less favorable entities such as salivary duct carcinomas and adenocarcinomas NOS (not otherwise specified) yielded higher expressions. CONCLUSIONS: LAG3 is particularly detectable in aggressive entities and advanced tumors. Hence, LAG3 inhibition poses a potential targeted therapy for advanced and metastatic SGCs.

TORS in HPV-Positive Tumors-The New Standard?

In this chapter, we discuss implications of tumor site and tumor microenvironment properties of human papilloma virus (HPV)-associated cancer formation with special emphasis on the therapeutic modality of transoral robotic surgery (TORS). Over the past years, the development of robotic systems has improved, and therefore, its use in the surgical treatment of HNSCC has become a relevant treatment modality for many patients. Yet, there are limitations. Especially for endolaryngeal TORS procedures, additional technical development is mandatory, particularly with respect to visualization and manipulation. The Flex System has provided new additions that need to be further evaluated. TORS systems are going to improve technical issues and therefore reduce patient morbidity, surgical handling and treatment costs. The developed systems have to be tested and evaluated in prospective trials in order to be able to identify benefits and disadvantages in patient care. With respect to HPV-related OPSCC, TORS has become a valuable surgical alternative for an increasing number of patients.

[Advances in transoral robotic surgery]. / Fortschritte in der transoralen roboterassistierten Chirurgie.

BACKGROUND: The role of transoral robotic surgery (TORS) in the treatment of head and neck tumors has expanded in the last decade. OBJECTIVES: We present the development and current advances in TORS along with the current indications and contraindications, and describe future developments. METHODS: We present our own studies and review those in the literature. RESULTS: Since approval of the da Vinci® system, the number of TORS cases has increased significantly. The main indications are tumors of the oropharynx and supraglottis. Most published studies are retrospective case series with no control group. In addition to the further development of the da Vinci® system, the introduction of the Flex®-system is a significant progression. The costs of using robotic systems are high. CONCLUSIONS: Technical improvement of robotic systems and the development of new surgical techniques will further expand the indications for TORS. The value of TORS needs to be assessed in prospective controlled studies.

[Immunotherapy in head and neck cancer]. / Immuntherapie bei Kopf-Hals-Karzinomen.

The physiological immune response to malignant cells is based on the interaction of antigen-presenting cells, such as dendritic cells and macrophages, with T and B lymphocytes. CD8(+) effector and natural killer cells are primarily responsible for tumor cell lysis. Tumor cells exploit several mechanisms to influence the body's immune system and promote development and progress of solid head and neck malignancies. Via regulatory T cells, myeloid-derived suppressor cells, tumor-associated macrophages, and cancer-associated fibroblasts, tumor cells promote development of suppressive signaling pathways that enable tumor progression. Novel immune therapeutics aim to influence these signaling pathways. Current studies are investigating agents which influence immune-stimulating or immune-suppressive cytokines, as well as drug-based Toll-like receptor activation and vaccination in head and neck cancer. Development of monoclonal antibodies allows for direct and highly specific binding of therapeutics to cell receptors - recently discovered immune checkpoint receptors are particularly intriguing targets. Monoclonal antibodies directed specifically toward T cell-stimulating receptors such as CD28 and CD134, or immunosuppressive receptors CTLA-4 and PD-1, are currently under investigation and have shown promising results.

[Diseases of the cervical lymph nodes in childhood]. / Erkrankungen der Halslymphknoten im Kindesalter.

The lymph nodes are an essential part of the body's immune system and as such are affected in many infectious, autoimmune, metabolic and malignant diseases. The cervical lymph nodes are particularly important because they are the first drainage stations for key points of contact with the outside world (mouth/throat/nose/eyes/ears/respiratory system) - a critical aspect especially among children - and can represent an early clinical sign in their exposed position on a child's slim neck. Involvement of the lymph nodes in multiple conditions is accompanied by a correspondingly large number of available diagnostic procedures. In the interests of time, patient wellbeing and cost, a careful choice of these must be made to permit appropriate treatment. The basis of diagnostic decisions is a detailed anamnesis and clinical examination. Sonography also plays an important role in differential diagnosis of lymph node swelling in children and is useful in answering one of the critical diagnostic questions: is there a suspicion of malignancy? If so, full dissection of the most conspicuous lymph node may be necessary to obtain histological confirmation. Diagnosis and treatment of childhood cervical lymph node disorders present the attending pediatric and ENT physicians with some particular challenges. The spectrum of differential diagnoses and the varying degrees of clinical relevance - from banal infections to malignant diseases - demand a clear and considered approach to the child's individual clinical presentation. Such an approach is described in the following paper.

EGFR-targeted mAb therapy modulates autophagy in head and neck squamous cell carcinoma through NLRX1-TUFM protein complex.

Epidermal growth factor receptor (EGFR)-targeted therapy in head and neck squamous cell carcinoma (HNSCC) patients frequently results in tumor resistance to treatment. Autophagy is an emerging underlying resistance mechanism, however, the molecular autophagy machinery in HNSCC cells and potential biomarkers of patient response to EGFR-targeted therapy remain insufficiently characterized. Here we show that the EGFR blocking with cetuximab leads to varied autophagic responses, which modulate cancer cell susceptibility to EGFR inhibition. Inhibition of autophagy sensitizes HNSCC cells to EGFR blockade. Importantly, we identify a novel signaling hub centering on the NLRX1 (nucleotide-binding, lots of leucine-rich repeats-containing protein member X1)-TUFM (Tu translation elongation factor mitochondrial) protein complex, promoting autophagic flux. Defects in the expression of either NLRX1 or TUFM result in compromised autophagy when treated with EGFR inhibitors. As a previously undefined autophagy-promoting mechanism, we found that TUFM serves as a novel anchorage site, recruiting Beclin-1 to mitochondria, promoting its polyubiquitination, and interfering with its interaction with Rubicon. This protein complex is also essential for endoplasmic reticulum stress signaling induction, possibly as an additional mechanism to promote autophagy. Utilizing tumor specimens from a novel neoadjuvant clinical trial, we show that increased expression of the autophagy adaptor protein, SQSTM1/p62, is associated with poor response to cetuximab therapy. These findings expand our understanding of the components involved in HNSCC autophagy machinery that responds to EGFR inhibitors, and suggest potential combinatorial approaches to enhance its therapeutic efficacy.