[Oncologic follow-up in head and neck cancer patients]. / Onkologische Nachsorge von Kopf-Hals-Tumor-Patienten.

Despite medical treatment according to evidence-based guidelines, approximately 25-30% of all head and neck tumor patients suffer a disease relapse, depending on tumor stage and entity. The primary goal of systematic follow-up examinations is early detection and treatment of recurrent tumors or metachronous secondary tumors, but it also serves to rule out distant metastasis. Secondary goals are the diagnosis and management of treatment-associated side effects to optimize quality of life. Because of an especially high relapse risk in the first 2 years after treatment, close-knit clinical controls are recommended, e.g., quarterly. Later on, the clinical control interval can be extended to 6 months. Cross-sectional diagnostic imaging of the primary tumor region is performed annually and when screening for possible distant metastases, or upon clinical suspicion of recurrence. After 5 years without tumor recurrence, the structured clinical follow-up is usually completed.

Changes in circulating exosome molecular profiles following surgery/(chemo)radiotherapy: early detection of response in head and neck cancer patients.

BACKGROUND: Head and neck cancers (HNSCC) are highly immunosuppressive. Plasma-derived exosomes of HNSCC patients carry immunomodulatory molecules, and their cargo correlates with clinical parameters. Here, we evaluated the exosomal molecular profile for early detection of treatment failure in locally advanced HNSCC patients treated with conventional therapy. METHODS: Plasma from 17 HNSCC patients was collected before, during, and after treatment by surgery with adjuvant (chemo)radiation and at recurrence. Exosomes were isolated by size-exclusion chromatography. Total exosomal protein (TEP) was used to estimate exosome load and on-bead flow cytometry to evaluate relative fluorescence intensity (RFI) of tumour-associated and immunoregulatory proteins on exosomes. Exosomal effects on the activity of and adenosine production by T cells was assessed by flow cytometry and mass spectrometry. RESULTS: TEP and the ratio of tumour-/immune-cell-derived exosomes varied during and after therapy with an overall decrease in the tumour-free follow-up but an increase at recurrence. RFI values of immunoregulatory proteins on exosomes, their ability for T cell inhibition and adenosine production changed during and after therapy. PD-L1 was the earliest discriminator for treatment failure and disease-free survival. CONCLUSIONS: Monitoring of plasma exosomes during therapy represents a promising opportunity for early detection of treatment failure and risk stratification to delay/avoid recurrence.

Influence of travel burden on tumor classification and survival of head and neck cancer patients.

PURPOSE: Cancer patients have to overcome various barriers to obtain diagnostics and treatment at head and neck cancer centers. Travel distance to a specialized hospital may result in psychosocial and financial distress, thus interfering with diagnostics, treatment, and follow-up care. In this study, we have aimed to analyze the association of travel distance with cTNM status, UICC stage at primary diagnosis, and survival outcomes of head and neck cancer (HNC) patients. METHODS: We have analyzed data of 1921 consecutive HNC patients diagnosed between 2014 and 2019 at the head and neck cancer center of the Comprehensive Cancer Center Ulm (CCCU), Germany. Postal code-based travel distance calculation in kilometers, TNM status, and UICC stage were recorded at initial diagnosis. The assembly of travel distance-related groups (short, intermediate, long-distance) has been investigated. Moreover, group-related survival and recurrence analysis have been performed. RESULTS: In contrast to observations from overseas, no association of travel distance and higher cTNM status or UICC stage at primary diagnosis has been observed. Furthermore, no significant differences for recurrence-free survival and overall survival by travel distance were detected. CONCLUSION: In southern Germany, travel distance to head and neck cancer centers seems to be tolerable. Travel burden is not synonymous with travel distance alone but also involves sociodemographic, monetary, and disease-specific aspects as well as accessibility to proper infrastructure of transport and health care system.

[Tumor biology of oropharyngeal carcinoma]. / Tumorbiologie des Oropharynxkarzinoms.

BACKGROUND: Etiologically, oropharyngeal squamous cell carcinoma (OPSCC) can be divided into OPSCC caused by noxious agents and human papillomavirus (HPV)-driven carcinoma. These types differ with regard to clinical features and prognosis-differences which are rooted in the underlying molecular biology of the tumor. OBJECTIVE: The aim of this work is to provide an overview of the molecular biological characteristics of the genetics, epigenetics, and immunology of OPSCC. MATERIALS AND METHODS: A literature review was performed on a selection of genetic, epigenetic, and immunological factors characterizing OPSCC. RESULTS: The understanding of genetic aberrations and their consequences for cancerogenesis and tumor biology is increasing. Epigenetic phenomena are complementing functional relationships. However, epigenetic mechanisms of gene regulation are complex and much research is still required in this field. Immunological aspects of cancer molecular biology have moved into the focus in light of recent advances in the field of immunotherapy. CONCLUSION: The tumor biology of OPSCC is primarily defined by its HPV status. Additionally, HPV-independent genetic, epigenetic, and immunological signatures are being defined. From these advances, rationales for new treatment concepts may evolve.

Age-related changes in T lymphocytes of patients with head and neck squamous cell carcinoma.

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.

[Oncoimmunology in old age]. / Onkoimmunologie im Alter.

Physiological aging processes of the immune system are associated with an increased susceptibility to infectious, autoimmune and tumor diseases. In accordance with the general demographic development the number of tumor patients in advanced age also increases. An end to this development is not yet foreseeable. In tumor treatment, immunotherapy with checkpoint inhibitors is becoming increasingly more important; however, only a few studies on the efficacy and side-effect profiles in older patients exist so far. In this review article the changes in the immune system in old age and the influence on carcinogenesis are discussed. In addition, the current state of research on the immunotherapy of patients in advanced age who suffer from head and neck cancer is presented.

Adenosine production in mesenchymal stromal cells in relation to their developmental status.

BACKGROUND: Mesenchymal stromal cells (MSC) are multipotent progenitor cells found in the tumor microenvironment. They have an innate and regulatory immune activity, and they are able to produce immunosuppressive adenosine (ADO) via their ectonucleotidases CD39 and CD73. The present study explores ADO metabolism of MSC in relation to their developmental status. METHODS: We analyzed MSC (n = 6), chondrogenic progenitor cells (CPC, n = 8), and chondrocytes (n = 8) for surface markers by flow cytometry. The ability to hydrolyze ATP and to produce ADO was tested by luminescence assays and mass spectrometry. RESULTS: Significant differences in the surface marker expression of MSC, CPC, and chondrocytes were seen. While the expression of CD73 was observed to be the same on all cell types, the expression of the ectonucleotidase CD39 was significantly increased on MSC. Consequently, production of ADO was most abundant in MSC as compared with chondrocytes and CPC. CONCLUSION: Mesenchymal stromal cells are potent producers of ADO and are, therefore, able to increase immunosuppression. As MSC differentiate into chondrocytes, they lose this ability and may take on other functions.

[Update on HPV-associated head and neck cancer-highlights from the 2019 ASCO Annual Meeting]. / Update zu HPV-assoziierten Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2019.

At this year's Annual Meeting of the American Society for Clinical Oncology (ASCO), the keyword search "HPV-associated head and neck cancer" resulted in 920 hits-74% of the hits on human papillomavirus (HPV). This underlines the relevance of the topic. The spectrum ranged from validation and separation of the prognostic groups of patients with HPV-associated oropharyngeal carcinoma (OPSCC) according to TNM 8, to the characterization of new tumor markers and tumor mutational burden for possible de-escalation strategies to avoid toxicity of standard multimodal treatments. It has been shown that the separation of p16-positive OPSCC into Union for International Cancer Control (UICC) stages I and II with the current TNM 8 classification without further markers is not sufficiently successful to justify de-escalation strategies. Following publication of the results of the De-ESCALaTE- and RTOG-1016 trials in 2018, which confirm the current standard of care for p16-positive OPSCC, no further phase III studies on de-escalation were presented. In a presented prospective phase II study (NCT02281955), the radiotherapy dose was reduced to cumulative 60 Gy, whereby the simultaneous chemotherapy regimen with cisplatin 30 mg/m2 weekly is not standard of care and could be administered as an alternative to cisplatin cetuximab. Some work dealt with the oral and intestinal microbiota as prognostic markers or their treatment-related changes, particularly under immunotherapy. Modification seems to have a positive impact on the success of therapy. However, robust data are still lacking for the various modified treatments for HPV-associated OPSCC, which are needed before their implementation in daily practice.

[Treatment of head and neck squamous cell carcinoma recurrences and distant metastases : Highlights of the 2019 ASCO Meeting]. / Therapie der rezidivierten und fernmetastasierten Plattenepithelkarzinome des Kopf-Hals-Bereichs : Highlights des ASCO-Meetings 2019.

BACKGROUND: The contributions presented at this year's ASCO conference on treatment of recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) focused on systemic therapies, as in recent years. Two phase III studies-TPExtreme and Keynote-048-are expected to change clinical practice in first-line treatment of R/M-HNSCC. MATERIALS AND METHODS: Abstracts and presentations from this year's ASCO Annual Meeting on R/M-HNSCC were screened and checked for clinical relevance. RESULTS: TPExtreme, a randomized phase III trial, could show less toxicity and similar overall survival in patients treated with docetaxel, cisplatin, and cetuximab (TPEx regimen) compared to standard first-line therapy with the Extreme regimen (cisplatin, 5­fluorouracil [5-FU], cetuximab), albeit failing its endpoint of significantly improved survival. The randomized phase III Keynote-048 study could show a significant survival benefit in all patients treated with pembrolizumab, 5­FU, and cis-/carboplatin compared to Extreme. When selected patients (PD-L1 CPS ≥1 and ≥20) were treated with pembrolizumab monotherapy, they showed increased overall response rates in contrast to patients treated with Extreme. CONCLUSION: Based on the results of Keynote-048, pembrolizumab ± chemotherapy gained FDA approval as first-line treatment for R/M-HNSCC in the USA. Approval in Europe is expected soon and will probably have a strong impact on clinical routine.

[Laryngectomy-still state of the art?] / Die Laryngektomie ­ noch zeitgemäß?

Total laryngectomy provides a curative approach for patients with advanced laryngeal and hypopharyngeal cancer without distant metastasis. Especially in stage cT4a disease, laryngectomy is superior to primary radio(chemo)therapy in retrospective studies. Further relevant indications for the procedure are tumor-related laryngeal dysfunction such as dysphagia and aspiration, as well as cancer recurrence after primary radio(chemo)therapy. The surgical procedure is highly standardized, with an appropriate safety profile. The subsequent loss of voice must be compensated by voice rehabilitation (voice prosthesis, ructus). The current overview provides information about indications for laryngectomy, preoperative clinical diagnostics, the surgical procedure, complications, alternative treatment, rehabilitation, and prognosis. Total laryngectomy remains a standard procedure in modern head and neck oncology.

[Studies on radiotherapy of head and neck cancer : Highlights of the 2019 ASCO Annual Meeting]. / Strahlentherapeutische Studien bei Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Radiotherapy is an important treatment option in patients with head and neck. At this year's annual meeting of the American Society of Clinical Oncology (ASCO) in Chicago, results of several studies on radiotherapy in patients with head and neck cancer were presented. MATERIALS AND METHODS: All abstracts and presentations from this year's ASCO Annual Meeting on radiotherapy in patients with head and neck cancer were screened and the most interesting results selected for further review. RESULTS: The ORATOR trial compared primary surgery in patients with oropharyngeal carcinoma (OPSCC) with primary radiochemotherapy (RCT), particularly in terms of swallowing, for which superiority of RCT was demonstrated. Furthermore, results were presented on the question of optimal cisplatin dosage in patients receiving adjuvant RCT. Higher cisplatin doses showed better outcome. In patients with nasopharyngeal carcinoma (NPC), neoadjuvant chemotherapy before RCT is a comparable alternative to RCT followed by adjuvant chemotherapy. In addition, results of studies were presented that examined the tolerability of combining immunotherapy with radiotherapy in the first-line setting. CONCLUSION: The data presented show promising approaches for the further development of radiotherapy, particularly in terms of combined RCT as well as the optimal sequencing and dosing of systemic therapies.

[Salivary gland malignancies-highlights of the 2019 ASCO Annual Meeting]. / Maligne Speicheldrüsentumoren ­ Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: Due to their comparatively low incidence, salivary gland carcinomas have only been the subject of isolated clinical studies in recent years. In addition, surgery with/without adjuvant radiotherapy is considered standard treatment. Systemic therapies have received little attention and are only used for advanced and distantly metastasized salivary gland malignancies. OBJECTIVE: The contributions with the highest relevance for this year's meeting of the American Society of Clinical Oncology (ASCO) were to be reviewed. MATERIALS AND METHODS: A total of 12 contributions pertaining to clinical studies on salivary gland malignancies were identified, eight of which were classified as relevant for future changes to the therapeutic landscape. RESULTS: Three studies dealt with different combinations of a checkpoint blockade, and each showed a low response rate. In addition, studies on targeted therapies depending on the results of a mutation analysis and expression of HER2 or the androgen receptor were presented. CONCLUSION: A favorable response of HER2-positive salivary gland carcinomas to an antibody-drug conjugate could be shown. Furthermore, no convincing data regarding response to programmed cell death protein 1 (PD1)/programmed death ligand 1 (PD-L1) inhibitors in advanced salivary gland cancer were presented. Further studies and ideas for new treatment approaches will be needed to improve the therapeutic options for patients with salivary gland carcinoma.

[Immunotherapy for head and neck cancer : Highlights of the 2019 ASCO Annual Meeting]. / Immuntherapie von Kopf-Hals-Tumoren : Highlights der ASCO-Jahrestagung 2019.

BACKGROUND: In the field of immunotherapy of head and neck squamous cell carcinoma (HNSCC), a high level of study activity can still be observed. The results of the Keynote-048 study on first-line therapy with pembrolizumab were a highlight at this year's meeting of the American Society of Clinical Oncology (ASCO). MATERIALS AND METHODS: All abstracts and presentations on immunotherapy of head and neck tumors presented at ASCO 2019 were evaluated for relevance and the most interesting studies were summarized. RESULTS: The Keynote-048 study showed an improvement in overall survival with pembrolizumab monotherapy for patients with measurable programmed cell death ligand 1 (PD-L1) expression according to the combined positive score (CPS), and for the whole cohort with the combination of pembrolizumab and platin/5-fluorouracil (FU). The EAGLE study on durvalumab ± tremelimumab in second-line therapy did not demonstrate any improvement in response rates or overall survival compared to standard therapy. In addition, several new immunotherapeutic approaches and combinations were presented. CONCLUSION: The results of the Keynote-048 study have already led to the approval of pembrolizumab in the first line for platin-sensitive HNSCC in the USA and the expected approval in Europe will presumably change the therapeutic landscape in the long term. In the future, effective therapies for patients without a response to programmed cell death 1 (PD-1)/PD-L1 inhibition will be needed.

Polyfunctionality of CD4+ T lymphocytes is increased after chemoradiotherapy of head and neck squamous cell carcinoma.

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.

[Radiotherapeutic studies of head and neck cancer-highlights of the 2018 ASCO Annual Meeting]. / Strahlentherapeutische Studien bei Kopf-Hals-Tumoren ­ Highlights der ASCO-Jahrestagung 2018.

BACKGROUND: Radiotherapy is an important treatment option in patients with advanced head and neck cancer. At the 2018 Annual Meeting of the American Society of Clinical Oncology (ASCO), study results were presented that could further develop and modify existing therapy concepts in the future. MATERIALS AND METHODS: All ASCO abstracts and presentations concerning radiotherapy of head and neck cancer were screened and the most interesting abstracts were selected for further review. RESULTS: One major topic was the combination of radiation with immunotherapy. Presented trials included combination treatment of epidermal growth factor receptor (EGFR) antibodies and platin-based chemoradiotherapy, as well as programmed cell death protein 1 (PD-1) antibodies in combination with platin-based chemoradiotherapy or cetuximab radiotherapy. In one study, the impact of adjuvant (chemo)radiotherapy for overall survival of human papillomavirus (HPV)-associated head and neck cancer with low to intermediate risk was analyzed. Additionally, studies focusing on the prophylaxis or reduction of radiation-mediated oral mucositis were presented. CONCLUSION: The data presented do not justify a change of current treatment paradigms just yet. However, interesting developments can be expected in the coming years, particularly in the field of immunotherapy.

[Immunotherapy highlights of the ASCO annual meeting 2018 for head and neck cancers]. / Highlights der ASCO Jahrestagung 2018 zur Immuntherapie von Kopf-Hals-Tumoren.

BACKGROUND: Immunotherapeutic strategies are becoming increasingly more important for head and neck cancer and numerous clinical trials were presented at the annual meeting of the American Society of Clinical Oncology (ASCO) 2018. OBJECTIVE: In this review the most interesting clinical trials and trial results for immunotherapy of head and neck cancer are summarized. MATERIAL AND METHODS: All abstracts and presentations on immunotherapy of head and neck cancer at the annual meeting of the ASCO 2018 were screened to select the most interesting trials for a more detailed analysis. RESULTS: For head and neck cancer, practice changing phase III trial results were missing, but several noteworthy new strategies and trial results for immunotherapy were presented. Neoadjuvant immunotherapy trials, results concerning immunotherapy in old age, prognostic implications of immune-mediated adverse events and new immunotherapy combinations are summarized in this article. CONCLUSION: The role of immunotherapy for the treatment of head and neck cancer is markedly increasing. Many pioneering trials are currently ongoing, in the phase of data analysis or in planning.

[Update on HPV-associated head and neck cancer-highlights of the 2018 ASCO Annual Meeting]. / Update zu HPV-assoziierten Kopf-Hals-Karzinomen ­ Highlights der ASCO-Jahrestagung 2018.

Rising incidence rates in human papillomavirus (HPV)-associated oropharyngeal squamous cell carcinoma (OPSCC) and a significantly improved prognosis have brought this entity into scientific focus. At this year's American Society of Clinical Oncology (ASCO) Annual Meeting, 291 studies with the keyword "HPV" were presented, the majority of which were in head and neck cancer. Due to high rates of late toxicities after conventional therapy, de-intensified treatment concepts are being increasingly discussed, although data from prospective phase III studies were not presented. Retrospective data on the latest TNM staging (downstaging in many HPV-associated patients) and other risk stratification systems were presented. HPV diagnostics based solely on p16 immunohistochemistry were discussed. Many groups presented work on the HPV association and its prognostic relevance not only in oropharyngeal carcinoma, but also in oral cavity, hypopharyngeal, and locally advanced laryngeal squamous cell carcinoma. New prognostic biomarkers such as methylation signatures appear to be promising. New data suggest equal survival rates in HPV-associated stage I OPSCC treated with surgery alone in comparison to patients who received adjuvant therapy after surgery. A possible negative effect on overall survival in stage III HPV-associated OPSCC with a cisplatin dose ≤200 mg/m2 was discussed. Results of de-escalation studies are urgently awaited, in order to be able to treat HPV-associated OPSCC patients as precisely and as specifically as possible and ensure long-term quality of life.

Differential transcriptome of tolerogenic versus inflammatory dendritic cells points to modulated T1D genetic risk and enriched immune regulation.

Tolerogenic dendritic cells (tolDCs) are assessed as immunomodulatory adjuvants to regulate autoimmunity. The underlying gene expression endorsing their regulatory features remains ill-defined. Using deep mRNA sequencing, we compared transcriptomes of 1,25-dihydroxyvitaminD3/dexametasone-modulated tolDCs with that of non-modulated mature inflammatory DCs (mDCs). Differentially expressed genes controlled cellular interactions, metabolic pathways and endorse tolDCs with the capacity to regulate cell activation through nutrient and signal deprivation, collectively gearing tolDCs into tolerogenic immune regulators. Gene expression differences correlated with protein expression, designating low CD86 and high CD52 on the cell surface as superior discriminators between tolDCs and mDCs. Of 37 candidate genes conferring risk to developing type 1 diabetes (T1D), 11 genes differentially expressed in tolDCs and mDCs regulated immune response and antigen-presenting activity. Differential-expressed transcripts of candidate risk loci for T1D suggest a role of these 'risk genes' in immune regulation, which targeting may modulate the genetic contribution to autoimmunity.

Response Evaluation in Head and Neck Oncology: Definition and Prediction.

Curative treatment of head and neck squamous cell carcinoma includes surgery and/or (chemo)radiation, whereas in the palliative setting, chemotherapy and/or immunotherapy represent(s) the standard approach. With regard to quality control, methods for determining treatment response are sorely needed. For surgical therapy, histopathology is the standard quality control. Established criteria for high-risk patients include resection margins of the primary tumor and extracapsular extension of lymph node metastases. After definitive chemoradiation, treatment response is generally evaluated by tomographic imaging combined with endoscopy including re-biopsy of the tumor region. Single-cycle induction chemotherapy may be used to determine the radiosensitivity of tumors, helping to define surgical and nonsurgical treatment options. Innovative approaches with implications for prognosis include the analysis of immune infiltrates, liquid biopsy, molecular characterization (proteomics, genomics), molecular and functional imaging (PET-CT, PET-MRI), as well as advanced imaging data analysis (radio[geno]mics/texture analysis). Human papilloma virus, as a prognostically relevant parameter, is currently being investigated for de-escalation strategies. With regard to the extended personalization of oncologic therapy, markers predicting treatment response are desirable and seem to be important, also from a socioeconomic perspective.

Variation in the CTLA4 3'UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a protein receptor that downregulates the immune system. CTLA4 gene variants associate with various autoimmune diseases, including type 1 diabetes. Fine mapping of the genetic risk has shown that the genomic region near CTLA4 marked by the single-nucleotide polymorphism (SNP) CT60A/G (rs3087243) acts as a susceptibility factor. Yet, the functional basis for the increased susceptibility conferred by rs3087243 remains unclear. We demonstrate that the length of the dinucleotide (AT)n repeat within the CTLA4 3' untranslated region (3'UTR) strongly associates with the risk of SNP CT60A/G (P<6.5 × 10(-72)). Genomic (AT)n repeat length inversely correlated with CTLA4 messenger RNA (mRNA) and protein levels in islet autoreactive T-cell lines. Transfer of a long (AT)n element into T cells lead to a reduction of mRNA compared to a short (AT)n element. Thus, this study provides evidence for a role of the CTLA4 3'UTR (AT)n repeat in the increased genetic risk for islet autoimmunity associated with the CTLA4 locus.