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Introduction: The number of aging cancer patients has increased continuously and will do so further in the future. The immune system of elderly people experiences critical changes over the time. Therefore, tumor-induced changes in the immune system are believed to differ in young and elderly cancer patients as well. Methods: The effect of aging on the immune system was measured in peripheral blood lymphocytes (PBL) of healthy volunteers (n = 48, 21–84 yrs.) divided into three different age groups. Seventy years was set as a cut-off for defining subjects as elderly. Results were compared to two groups of adult cancer patients, which donated PBL and tumor infiltrating lymphocytes (TIL): young cancer patients (40–69 yrs.; blood: n = 13; TIL: n = 17) and elderly cancer patients (70–90 yrs.; blood: n = 20; TIL: n = 15) with head and neck squamous cell carcinoma (HNSCC). Frequencies and phenotypes of CD4+ and CD8+ T cells as well as regulatory T cells (Treg) were assessed by flow cytometry. Results: We observed lower frequencies of CD8+ cytotoxic T cells during aging in both groups. Frequencies of tumor infiltrating regulatory T cells were significantly higher than in the peripheral blood but showed a significant decline in older tumor patients. With increasing age, expression of immunosuppressive CD73 and CCR7 was lower and expression of PD1 elevated on peripheral T cells in healthy volunteers and tumor patients. Conclusion: Immunosenescence takes place in healthy donors and cancer patients. Our results suggest that in elderly tumor patients, the immune system is impaired and the tumor-induced immune escape is less pronounced. The increased expression of PD1 implies the potential for effective immunotherapies in elderly, as treatment with checkpoint inhibitors could be more beneficial for elderly HNSCC patients. [ABSTRACT FROM AUTHOR]

Purpose: Adenoid cystic carcinoma (ACC) of the head and neck is a rare and highly malignant tumor, characterized by perineural growth and early distant metastases. The composition of immune cells in the peripheral blood and the tumor microenvironment is critical to tumor growth and control. However, little is known about the frequency and function of the relevant immune cell subsets in this entity. Methods: In ACC patients (n = 11) and matched healthy donors (n = 11), the frequency of peripheral blood T and B cells was measured by flow cytometry at different treatment stages of disease (24 samples). Cells were further characterized by their expression of CCR7, PD-1, CD39 and CD73. Tumor-infiltrating lymphocytes (TIL) were analyzed by immunohistochemistry for ten patients and for three patients by flow cytometry. Results: CD4+ T cells had significantly lower frequency after radiotherapy (RT). All other cell frequencies, including Treg, were stable through course of the disease. In B cells, CD73 was reduced after RT. CCR7 expression on T and B cells in patients with relapse/metastases (R/M) differed significantly from patients with active disease. PD-1 remained stable. Treg were more present in TIL compared to peripheral blood. Conclusion: Composition of lymphocyte subgroups behaves similar to squamous cell carcinoma in the head and neck, except for Treg, which remained stable. Nevertheless, the CD4+/Treg ratio was lower after RT, which could stand for an immunosuppressive effect in these patients. Therefore, it could be beneficial treating ACC with combined RT and immunomodulatory drugs. [ABSTRACT FROM AUTHOR]

Summary: Exosomes in plasma of head and neck squamous cell carcinoma (HNSCC) patients comprise subsets of vesicles derived from various cells. Recently, we separated CD3(+) from CD3(–) exosomes by immune capture. CD3(–) exosomes were largely tumour‐derived (CD44v3+). Both subsets carried immunosuppressive proteins and inhibited functions of human immune cells. The role of these subsets in immune cell reprogramming by the tumour was investigated by focusing on the adenosine pathway components. Spontaneous adenosine production by CD3(+) or CD3(–) exosomes was measured by mass spectrometry, as was the production of adenosine by CD4+CD39+ regulatory T cells (Treg) co‐incubated with these exosomes. The highest level of CD39/CD73 ectoenzymes and of adenosine production was found in CD3(–) exosomes in patients with the stages III/IV HNSCCs). Also, the production of 5′‐AMP and purines was significantly higher in Treg co‐incubated with CD3(–) than CD3(+) exosomes. Consistently, CD26 and adenosine deaminase (ADA) levels were higher in CD3(+) than CD3(–) exosomes. ADA and CD26 levels in CD3(+) exosomes were significantly higher in patients with early (stages I/II) than advanced (stages III/IV) disease. HNSCC patients receiving and responding to photodynamic therapy had increased ADA levels in CD3(+) exosomes with no increase in CD3(–) exosomes. The opposite roles of CD3(+) ADA+CD26+ and CD3(–)CD44v3+ adenosine‐producing exosomes in early versus advanced HNSCC suggest that, like their parent cells, these exosomes serve as surrogates of immune suppression in cancer. [ABSTRACT FROM AUTHOR]

Summary: Head and neck squamous cell carcinoma (HNSCC) is a highly immunosuppressive malignancy. Exosomes in HNSCC patients' plasma are enriched in inhibitory cargo and mediate immunosuppression. As these exosomes are products of various cells, the cellular origin of immunoregulatory proteins they carry is unknown. To test whether tumour‐ or T cell‐derived exosomes in patients' plasma are immunosuppressive and impact upon disease activity, we separated CD3(–) from CD3(+) exosomes by immunocapture using anti‐CD3 antibodies. The exosome protein cargo was evaluated for immunoregulatory proteins using on‐bead flow cytometry. Tumour protein‐enriched CD3(–) exosomes were CD44v3(+). Surprisingly, mean levels of programmed death ligand 1 (PD‐L1), cytotoxic T lymphocyte antigen 4 (CTLA‐4) and cyclooxygenase‐2 (COX‐2) were similar in CD3(+) and CD3(–) exosomes, although the latter induced higher (P < 0·0025) ex‐vivo apoptosis of CD8(+) T cells and greater (P < 0·005) conversion of CD4+ T cells to CD4(+)CD39(+) regulatory T cells (Treg). CD3(+) and CD3(–) exosomes carrying high levels of immunosuppressive proteins were highly effective in mediating these functions. Exosomes of patients with Union for International Cancer Control (UICC) stages III/IV disease had higher levels of PD‐L1 and COX‐2 than stages I/II patients (P < 0·005). Patients with nodal involvement had exosomes with the higher inhibitory protein content than N0 patients (P < 0·03). CD3(+) and CD3(–) exosomes of HNSCC patients had higher PD‐L1, COX‐2 and CD15s levels than healthy donors' exosomes (P < 0·009), although levels of immunostimulatory OX40 or OX40L were not different. By isolating CD3(–)/CD44v3‐enriched and CD3(+) exosomes from plasma, the cellular origins of immunoregulatory proteins they carry were identified. Association of exosome molecular profiles with disease progression supports the exosome potential as future cancer biomarkers. [ABSTRACT FROM AUTHOR]

Background: For head and neck squamous cell cancer (HNSCC), standard therapy consists of surgery, radiation, and/or chemotherapy. Antineoplastic immunotherapy could be an option in an adjuvant setting and is already in palliation. A functional immune system is a prerequisite for successful immunotherapy. However, effects of the standard-of-care therapy on the patients' immune system are not fully understood.Methods: Peripheral blood mononuclear cells (PBMC) were collected from patients with HNSCC (n = 37) and healthy controls (n = 10). PBMC were stimulated with staphylococcal enterotoxin B (SEB). Simultaneous expression of various cytokines was measured in CD4+ and CD8+ T cells by multicolor flow cytometry, and polyfunctional cytokine expression profiles were determined on a single-cell basis.Results: Expression levels of all measured cytokines in CD4+ T cells were higher in patients after chemoradiotherapy (CRT) as compared to untreated HNSCC patients or normal controls. After CRT, the frequency of polyfunctional CD4+ T cells, which simultaneously expressed multiple cytokines, was significantly increased as compared to untreated patients (p < 0.01).Conclusion: CRT increases polyfunctionality of CD4+ T cells in HNSCC patients, suggesting that standard-of-care therapy can promote immune activity in immune cells. These polyfunctional CD4+ T cells in the blood of treated HNSCC patients are expected to be responsive to subsequent immunotherapeutic approaches. [ABSTRACT FROM AUTHOR]

Background: The incidence of synchronous bilateral tonsil carcinoma seems to be underreported. For adequate oncologic treatment, it is mandatory to remove all primaries to prevent recurrence or metachronic disease. The purpose of this manuscript is to provide a comprehensive review on this topic and to emphasize the need of bilateral tonsillectomy in cases of cancer of unknown primary (CUP) as well as in the case of a unilateral tonsillar carcinoma. Material and methods: A systematic review of the literature was performed for "bilateral tonsillar neoplasm", "synchronous cancer of the oropharynx" and "cancer of unknown primary in head and neck". Results: We present a clinical case with bilateral tonsillar carcinoma in initially suggested cancer of unknown primary. Clinically, both tonsillar sites were unsuspicious, but in PET/CT an ipsilateral enhancement of the tonsil area was detected. The pathological work up of bilateral tonsillectomy specimens revealed bilateral squamous cell carcinoma with HPV-type 16 positivity. The review of the literature revealed 29 cases of bilateral tonsil cancer. Conclusion: The handling of tonsillar tissue in the frame of panendoscopy in the case of CUP is still controversial. We recommend a bilateral tonsillectomy as a routine procedure for cancer of unknown primary as well as unilateral tonsillar carcinoma. Herewith the detrimental consequences of occult metachronous contralateral tonsillar carcinoma can be prevented. [ABSTRACT FROM AUTHOR]

The competent immune system controls disease effectively due to induction, function, and regulation of effector lymphocytes. Immunosurveillance is exerted mostly by cytotoxic T-lymphocytes (CTLs) while specific immune suppression is associated with tumor malignancy and progression. In squamous cell carcinoma of the head and neck, the presence, activity, but also suppression of tumor-specific CTL have been demonstrated. Functional CTL may exert a selection pressure on the tumor cells that consecutively escape by a combination of molecular and cellular evasion mechanisms. Certain of these mechanisms target antitumor effector cells directly or indirectly by affecting cells that regulate CTL function. This results in the dysfunction or apoptosis of lymphocytes and dysregulated lymphocyte homeostasis. Another important tumor-escape mechanism is to avoid recognition by dysregulation of antigen processing and presentation. Thus, both induction of functional CTL and susceptibility of the tumor and its microenvironment to become T cell targets should be considered in CTL-based immunotherapy. [ABSTRACT FROM AUTHOR]

In this open uncontrolled phase I study, nine patients with stage III and IV squamous cell carcinoma of the head and neck (SCCHN) were treated with five administrations of the humanized antiepidermal growth factor receptor monoclonal antibody EMD 72000 in three consecutive ascending dose groups. Loading doses of 100 mg (group I), 200 mg (group II), and 400 mg (group III) were followed by four weekly maintenance doses of half the loading doses, i.e. 50, 100, and 200 mg, respectively. Two EMD 72000 administrations were scheduled before and three after surgery. The objectives of this trial were (a) to investigate the safety and toxicity of multiple EMD 72000 doses, (b) to determine the cumulative maximum tolerated dose of EMD 72000 at dosages between 300 mg and 1,200 mg, and (c) to determine the serum pharmacokinetics of EMD 72000. In total, 102 adverse events (AEs) were reported: five of toxicity grade 3, 18 of toxicity grade 2, 66 of toxicity grade 1, and 38 of toxicity grade 0. All AEs of toxicity grade 3 were considered to be not or remotely related to EMD 72000. The most frequent study drug-related AEs were fever and a transient elevation of liver enzymes. In all patients, the time to reach peak serum concentrations (tmax) was within 1-3 h of the start of each EMD 72000 infusion. Average peak serum concentrations (Cmax) after correction for dosage appeared to be dose-independent, whereas the half-life (t1/2) showed dose dependency. In conclusion, EMD 72000 was very well tolerated in patients with advanced stage SCCHN. The pharmacokinetic data from this trial suggest the feasibility of conducting future studies with weekly doses of 200 mg EMD 72000. [ABSTRACT FROM AUTHOR]