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OBJECTIVES: The eighth edition American Joint Committee on Cancer (AJCC) Staging incorporates significant changes to the seventh edition in the staging of oropharyngeal squamous cell carcinomas (OPSCC). An important change was the inclusion of OPSCC associated with the human papilloma virus (HPV). Our goal is to compare the performance of both staging systems for patients with HPV-selected and unselected clinical characteristics for OPSCC. METHODS: Using the Surveillance, Epidemiology, and End Results (SEER) database, 2004-2016, we identified patients with likely HPV-associated OPSCC based on surrogate markers (white males aged <65 years old with squamous cell carcinomas of the tonsil and base of tongue), excluding those who underwent surgery. We re-classified these patients using seventh and eighth edition staging for HPV-selected OPSCC and compared the prediction performance of both staging editions for overall survival (OS) and disease-specific survival (DSS). We performed the same analysis for clinically unselected patients with OPSCC. RESULTS: Our analysis included 9554 patients with a median follow-up of 67 months. Comparing the eighth versus seventh edition for our HPV-selected cohort, clinical staging changed for 92.3% of patients and 10-year OS was 62.2%, 61.2%, 35.3%, and 15.5% for Stage I, II, III, and IV, versus 52.9%, 59.2%, 61.6%, 55.1%, 38.3%, and 15.5% for stage I, II, III, IVA, IVB, and IVC, respectively. A similar pattern was observed for 10-year DSS. The concordance statistics for our HPV-selected cohort were improved for both AJCC 7 (0.6260) and AJCC 8 (0.6846) compared with the unselected cohort, 0.5860 and 0.6457 for AJCC 7 and 8, respectively. CONCLUSION: The overall performance of discrimination improved from AJCC 7 to AJCC 8 for both clinically selected and unselected patients, but more notably for our HPV-selected cohort. Despite the lack of statistically significant differentiation between Stages I and II in AJCC 8 in either groups, markedly improved discrimination was observed between Stages I/II, III, and IV in the HPV-selected cohort.
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Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Orofaríngeas , Infecções por Papillomavirus , Idoso , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Orofaríngeas/patologia , Papillomaviridae , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Prognóstico , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologiaRESUMO
Thyroid cancer development is driven by known point mutations or gene fusions found in â¼90% of cases, whereas driver mutations in the remaining tumors are unknown. The insulin-like growth factor 2 mRNA-binding protein 3 (IGF2BP3) plays an important role in cancer, yet the mechanisms of its activation in cancer cells remain poorly understood. Using whole-transcriptome and whole-genome analyses, we identified a recurrent fusion between the thyroid adenoma-associated (THADA) gene on chromosome 2 and the LOC389473 gene on chromosome 7 located 12 kb upstream of the IGF2BP3 gene. We show that THADA fusion to LOC389473 and other regions in the vicinity does not result in the formation of a chimeric protein but instead leads to strong overexpression of the full-length IGF2BP3 mRNA and protein, increased IGF2 translation and IGF1 receptor (IGF1R) signaling via PI3K and MAPK cascades, and promotion of cell proliferation, invasion, and transformation. THADA fusions and IGF2BP3 overexpression are found in â¼5% of thyroid cancers that lack any other driver mutations. We also find that strong IGF2BP3 overexpression via gene fusion, amplification, or other mechanisms occurs in 5 to 15% of several other cancer types. Finally, we provide in vitro and in vivo evidence that growth of IGF2BP3-driven cells and tumors may be blocked by IGF1R inhibition, raising the possibility that IGF2BP3 overexpression in cancer cells may predict an anti-IGF1R benefit.
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Regulação Neoplásica da Expressão Gênica , Proteínas de Neoplasias/genética , Proteínas de Fusão Oncogênica/genética , Proteínas de Ligação a RNA/genética , Receptores de Somatomedina/genética , Neoplasias da Glândula Tireoide/genética , Animais , Antineoplásicos/farmacologia , Linhagem Celular Tumoral , Transformação Celular Neoplásica , Feminino , Loci Gênicos , Estudo de Associação Genômica Ampla , Humanos , Imidazóis/farmacologia , Fator de Crescimento Insulin-Like II/genética , Fator de Crescimento Insulin-Like II/metabolismo , Camundongos , Camundongos Nus , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Neoplasias/metabolismo , Proteínas de Fusão Oncogênica/metabolismo , Fosfatidilinositol 3-Quinases/genética , Fosfatidilinositol 3-Quinases/metabolismo , Biossíntese de Proteínas , Inibidores de Proteínas Quinases/farmacologia , Pirazinas/farmacologia , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Proteínas de Ligação a RNA/metabolismo , Receptor IGF Tipo 1 , Receptores de Somatomedina/antagonistas & inibidores , Receptores de Somatomedina/metabolismo , Transdução de Sinais , Neoplasias da Glândula Tireoide/tratamento farmacológico , Neoplasias da Glândula Tireoide/metabolismo , Neoplasias da Glândula Tireoide/patologia , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
The incidence of human papillomavirus (HPV)-related head and neck squamous cell carcinoma has increased in recent decades, though HPV prevention vaccines may reduce this rise in the future. HPV-related cancers express the viral oncoproteins E6 and E7. The latter inactivates the tumor suppressor protein retinoblastoma (Rb), which leads to the overexpression of p16(INK4) protein, providing unique Ags for therapeutic HPV-specific cancer vaccination. We developed potential adenoviral vaccines that express a fusion protein of HPV-16 E6 and E7 (Ad.E6E7) alone or fused with p16 (Ad.E6E7p16) and also encoding an anti-programmed death (PD)-1 Ab. Human monocyte-derived dendritic cells (DC) transduced with Ad.E6E7 or Ad.E6E7p16 with or without Ad.αPD1 were used to activate autologous CD8 CTL in vitro. CTL responses were tested against naturally HPV-infected head and neck squamous cell carcinoma cells using IFN-γ ELISPOT and [(51)Cr]release assay. Surprisingly, stimulation and antitumor activity of CTL were increased after incubation with Ad.E6E7p16-transduced DC (DC.E6E7p16) compared with Ad.E6E7 (DC.E6E7), a result that may be due to an effect of p16 on cyclin-dependent kinase 4 levels and IL-12 secretion by DC. Moreover, the beneficial effect was most prominent when anti-PD-1 was introduced during the second round of stimulation (after initial priming). These data suggest that careful sequencing of Ad.E6E7.p16 with Ad.αPD1 could improve antitumor immunity against HPV-related tumors and that p16 may enhance the immunogenicity of DC, through cyclin-dependent pathways, Th1 cytokine secretion, and by adding a nonviral Ag highly overexpressed in HPV-induced cancers.
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Anticorpos/metabolismo , Linfócitos T CD8-Positivos/imunologia , Vacinas Anticâncer/administração & dosagem , Células Dendríticas/imunologia , Neoplasias de Cabeça e Pescoço/terapia , Papillomavirus Humano 16/imunologia , Neoplasias de Células Escamosas/terapia , Proteínas Oncogênicas Virais/metabolismo , Infecções por Papillomavirus/terapia , Proteínas Recombinantes de Fusão/metabolismo , Proteínas Repressoras/metabolismo , Adenoviridae/genética , Anticorpos/genética , Quinase 4 Dependente de Ciclina/metabolismo , Inibidor p16 de Quinase Dependente de Ciclina/genética , Inibidor p16 de Quinase Dependente de Ciclina/metabolismo , Citotoxicidade Imunológica , Células Dendríticas/transplante , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Interferon gama/metabolismo , Interleucina-12/metabolismo , Mutação/genética , Neoplasias de Células Escamosas/imunologia , Proteínas Oncogênicas Virais/genética , Infecções por Papillomavirus/imunologia , Receptor de Morte Celular Programada 1/imunologia , Proteínas Recombinantes de Fusão/genética , Proteínas Repressoras/genéticaRESUMO
BACKGROUND: Human papillomavirus 16 (HPV16) E6 antibodies may be an early marker of the diagnosis and recurrence of human papillomavirus-driven oropharyngeal cancer (HPV-OPC). METHODS: This study identified 161 incident oropharyngeal cancer (OPC) cases diagnosed at the University of Pittsburgh (2003-2013) with pretreatment serum. One hundred twelve had preexisting clinical HPV testing with p16 immunohistochemistry and HPV in situ hybridization (87 were dual-positive [HPV-OPC], and 25 were dual-negative [HPV-negative]); 62 had at least 1 posttreatment serum sample. Eighty-six of the 161 tumors were available for additional HPV16 DNA/RNA testing (45 were dual-positive [HPV16-OPC], and 19 were dual-negative [HPV16-negative). HPV16 E6 antibody testing was conducted with multiplex serology. The following were evaluated: 1) the sensitivity and specificity of HPV16 E6 serology for distinguishing HPV-OPC and HPV16-OPC from HPV-negative OPC, 2) HPV16 E6 antibody decay after treatment with linear models accommodating correlations in variance estimates, and 3) pre- and posttreatment HPV16 E6 levels and the risk of recurrence with Cox proportional hazards models. RESULTS: Seventy-eight of 87 HPV-OPCs were HPV16 E6-seropositive (sensitivity, 89.7%; 95% confidence interval [CI], 81.3%-95.2%), and 24 of 25 HPV-negative OPCs were HPV16 E6-seronegative (specificity, 96.0%; 95% CI, 79.6%-99.9%). Forty-two of 45 HPV16-OPCs were HPV16 E6-seropositive (sensitivity, 93.3%; 95% CI, 81.7%-98.6%), and 18 of 19 HPV16-negative OPCs were HPV16 E6-seronegative (specificity, 94.7%; 95% CI, 74.0%-99.9%). Posttreatment HPV16 E6 antibody levels did not decrease significantly from the baseline (P = .575; median follow-up, 307 days) and were not associated with the risk of recurrence. However, pretreatment HPV16 E6 seropositivity was associated with an 86% reduced risk of local/regional recurrence (hazard ratio, 0.14; 95% CI, 0.03-0.68; P = .015). CONCLUSIONS: HPV16 E6 antibodies may have potential clinical utility for the diagnosis and/or prognosis of HPV-OPC. Cancer 2017;123:4382-90. © 2017 American Cancer Society.
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Anticorpos Antivirais/sangue , Proteínas Oncogênicas Virais/imunologia , Neoplasias Orofaríngeas/diagnóstico , Infecções por Papillomavirus/diagnóstico , Proteínas Repressoras/imunologia , Transformação Celular Viral/imunologia , Feminino , Papillomavirus Humano 16/imunologia , Humanos , Imuno-Histoquímica , Masculino , Pessoa de Meia-Idade , Neoplasias Orofaríngeas/sangue , Neoplasias Orofaríngeas/patologia , Neoplasias Orofaríngeas/virologia , Infecções por Papillomavirus/sangue , Infecções por Papillomavirus/complicações , Infecções por Papillomavirus/patologia , Valor Preditivo dos Testes , Prognóstico , Recidiva , Sensibilidade e EspecificidadeRESUMO
Thyroid cancer is a common endocrine malignancy that encompasses well-differentiated as well as dedifferentiated cancer types. The latter tumors have high mortality and lack effective therapies. Using a paired-end RNA-sequencing approach, we report the discovery of rearrangements involving the anaplastic lymphoma kinase (ALK) gene in thyroid cancer. The most common of these involves a fusion between ALK and the striatin (STRN) gene, which is the result of a complex rearrangement involving the short arm of chromosome 2. STRN-ALK leads to constitutive activation of ALK kinase via dimerization mediated by the coiled-coil domain of STRN and to a kinase-dependent, thyroid-stimulating hormone-independent proliferation of thyroid cells. Moreover, expression of STRN-ALK transforms cells in vitro and induces tumor formation in nude mice. The kinase activity of STRN-ALK and the ALK-induced cell growth can be blocked by the ALK inhibitors crizotinib and TAE684. In addition to well-differentiated papillary cancer, STRN-ALK was found with a higher prevalence in poorly differentiated and anaplastic thyroid cancers, and it did not overlap with other known driver mutations in these tumors. Our data demonstrate that STRN-ALK fusion occurs in a subset of patients with highly aggressive types of thyroid cancer and provide initial evidence suggesting that it may represent a therapeutic target for these patients.
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Proteínas de Ligação a Calmodulina/genética , Fusão Gênica/genética , Proteínas de Membrana/genética , Proteínas do Tecido Nervoso/genética , Receptores Proteína Tirosina Quinases/genética , Neoplasias da Glândula Tireoide/genética , Transcriptoma/genética , Quinase do Linfoma Anaplásico , Sequência de Bases , Western Blotting , Crizotinibe , Células HEK293 , Humanos , Imuno-Histoquímica , Hibridização in Situ Fluorescente , Dados de Sequência Molecular , Pirazóis , Piridinas , Pirimidinas , Reação em Cadeia da Polimerase em Tempo Real , Receptores Proteína Tirosina Quinases/antagonistas & inibidores , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Análise de Sequência de RNARESUMO
Head and neck squamous cell carcinoma (HNSCC) is a devastating disease for which new treatments, such as immunotherapy are needed. Synthetic double-stranded RNAs, which activate toll-like receptor 3 (TLR3), have been used as potent adjuvants in cancer immunotherapy by triggering a proapoptotic response in cancer cells. A better understanding of the mechanism of TLR3-mediated apoptosis and its potential involvement in controlling tumor metastasis could lead to improvements in current treatment. Using paired, autologous primary and metastatic HNSCC cells we previously showed that metastatic, but not primary tumor-derived cells, were unable to activate prosurvival NF-κB in response to p(I):p(C) resulting in an enhanced apoptotic response. Here, we show that transcriptional downregulation of receptor-interacting serine/threonine-protein kinase 1 (RIPK1) in metastatic HNSCC cells causes a loss of TLR3-mediated NF-κB signaling, resulting in enhanced apoptosis. Loss of RIPK1 strongly correlates with metastatic disease in a cohort of HNSCC patients. This downregulation of RIPK1 is possibly mediated by enhanced methylation of the RIPK1 promoter in tumor cells and enhances protumorigenic properties such as cell migration. The results described here establish a novel mechanism of TLR3-mediated apoptosis in metastatic cells and may create new opportunities for using double stranded RNA to target metastatic tumor cells.
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Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Proteína Serina-Treonina Quinases de Interação com Receptores/metabolismo , Apoptose/genética , Carcinoma de Células Escamosas/metabolismo , Linhagem Celular Tumoral , Metilação de DNA , Regulação para Baixo , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Imunidade Inata/genética , NF-kappa B/metabolismo , Regiões Promotoras Genéticas , RNA de Cadeia Dupla/metabolismo , Proteína Serina-Treonina Quinases de Interação com Receptores/genética , Proteína Serina-Treonina Quinases de Interação com Receptores/imunologia , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço , Receptor 3 Toll-Like/metabolismoRESUMO
With cancer immunotherapy and precision medicine dynamically evolving, there is greater need for pre-clinical models that can better replicate the intact tumor and its complex tumor microenvironment (TME). Precision-cut tumor slices (PCTS) have recently emerged as an ex vivo human tumor model, offering the opportunity to study individual patient responses to targeted therapies, including immunotherapies. However, little is known about the physiologic status of PCTS and how culture conditions alter gene expression. In this study, we generated PCTS from head and neck cancers (HNC) and mesothelioma tumors (Meso) and undertook transcriptomic analyses to understand the changes that occur in the timeframe between PCTS generation and up to 72 h (hrs) in culture. Our findings showed major changes occurring during the first 24 h culture period of PCTS, involving genes related to wound healing, extracellular matrix, hypoxia, and IFNγ-dependent pathways in both tumor types, as well as tumor-specific changes. Collectively, our data provides an insight into PCTS physiology, which should be taken into consideration when designing PCTS studies, especially in the context of immunology and immunotherapy.
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Perfilação da Expressão Gênica , Microambiente Tumoral , Humanos , Microambiente Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/patologia , Neoplasias de Cabeça e Pescoço/terapia , Transcriptoma , Medicina de Precisão/métodos , Imunoterapia/métodosRESUMO
Precision-cut tumor slices (PCTS) have recently emerged as important ex vivo human tumor models, offering the opportunity to study individual patient responses to targeted immunotherapies, including CAR-T cell therapies. In this review, an outline of different human tumor models available in laboratory settings is provided, with a focus on the unique characteristics of PCTS. Standard PCTS generation and maintenance procedures are outlined, followed by an in-depth overview of PCTS utilization in preclinical research aiming to better understand the unique functional characteristics of cytotoxic T cells within human tumors. Furthermore, recent studies using PCTS as an ex vivo model for predicting patient responses to immunotherapies and other targeted therapies against solid tumors are thoroughly presented. Finally, the advantages and limitations of the PCTS models are discussed. PCTS are expected to gain momentum and be fully utilized as a significant tool towards better patient stratification and personalized medicine.
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The epidermal growth factor receptor (EGFR) is an important therapeutic target in head and neck squamous cell carcinomas (HNSCCs). EGFR-targeted agents including monoclonal antibodies and tyrosine kinase inhibitors have shown mixed results in clinical trials. To date, only cetuximab, an anti-EGFR monoclonal antibody, is approved for use in local/regional advanced and recurrent or metastatic HNSCC. This article reviews the mechanism of action of cetuximab and its antitumor immune effects and the data to support its use in HNSCC. It additionally provides an overview of other EGFR monoclonal antibodies and small molecule tyrosine kinase inhibitors that have been studied.
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Antineoplásicos , Neoplasias de Cabeça e Pescoço , Anticorpos Monoclonais Humanizados , Antineoplásicos/farmacologia , Cetuximab/farmacologia , Receptores ErbB , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , HumanosRESUMO
Head and neck squamous cell carcinomas (HNSCC) remain an important cause of global cancer morbidity and mortality. Historically, outcomes for patients with recurrent or metastatic disease were poor with limited treatment options. In recent decades, the demographic profile of this disease has evolved with an increase in human papilloma virus-associated oropharyngeal carcinoma and a decrease in tobacco-related disease. The treatment paradigm for HNSCC has rapidly evolved with identification of novel, immune-directed, therapeutic strategies that take advantage of immune dysregulation commonly seen in HNSCC. This review summarizes recent developments in this field and discusses emerging strategies for future therapies.
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Alphapapillomavirus , Neoplasias de Cabeça e Pescoço , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Fatores Imunológicos , Imunoterapia , Recidiva Local de Neoplasia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapiaRESUMO
OBJECTIVES/HYPOTHESIS: Recurrent respiratory papillomatosis (RRP) is a rare, potentially life-threatening, disease that impacts the voice, breathing, and quality of life of patients. Frequent surgical interventions may be needed to control symptoms. We examined the safety and efficacy of utilizing parenteral bevacizumab in the management of severe RRP in adults. STUDY DESIGN: This is a retrospective review of clinical management approaches in a group of patients with severe RRP defined as having a high disease burden, frequent need for debridement, and/or tracheobronchial disease. Patients were initially treated with 15 mg/kg of bevacizumab at 3-week intervals. Bevacizumab dosing and frequency was then individually titrated down. RESULTS: Fourteen adults received a median of 8.5 (range 2-17) bevacizumab infusions over approximately 24 months. All had a history of laryngeal RRP with 6/14 having additional tracheobronchial lesions. Patients required a median of 4 (range 2-11) procedures in the year prior to treatment. Only 3/10 (30%) patients who continued therapy required any additional procedures. Bevacizumab administration was generally well tolerated, with four patients discontinuing therapy. Medical reasons included severe epistaxis and hypertension and thrombocytopenia in an individual with systemic lupus erythematosus. Common side effects included hypertension (grade 2), headache (grades 1-2), elevated creatinine (grades 1-2), and epistaxis (grade 3). CONCLUSIONS: Intravenous bevacizumab for the primary treatment of severe RRP in adults appears clinically effective and safe. Expected and typically mild side effects related to bevacizumab were observed. Continued investigation of bevacizumab through a prospective clinical trial is warranted. LEVEL OF EVIDENCE: 4. Laryngoscope, 131:E921-E928, 2021.
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Inibidores da Angiogênese/administração & dosagem , Bevacizumab/administração & dosagem , Infecções por Papillomavirus/tratamento farmacológico , Infecções Respiratórias/tratamento farmacológico , Adulto , Idoso , Esquema de Medicação , Feminino , Humanos , Infusões Parenterais , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/patologia , Infecções Respiratórias/patologia , Estudos Retrospectivos , Resultado do Tratamento , Adulto JovemRESUMO
â¢Progestins can produce clinical benefit in a subset of women with metastatic endometrial cancer.â¢Corticosteroid-related effects of megestrol can cause morbidity over the long term.â¢Norethindrone is a progestin without corticosteroid side effects.â¢A switch from megestrol to norethindrone decreased toxicity with continued benefit.â¢A clinical trial of norethindrone for this population of patients would be welcome.
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PURPOSE: Cetuximab, an EGFR-specific antibody (mAb), modestly improves clinical outcome in patients with head and neck cancer (HNC). Cetuximab mediates natural killer (NK) cell:dendritic cell (DC) cross-talk by cross-linking FcγRIIIa, which is important for inducing antitumor cellular immunity. Cetuximab-activated NK cells upregulate the costimulatory receptor CD137 (4-1BB), which, when triggered by agonistic mAb urelumab, might enhance NK-cell functions, to promote T-cell-based immunity. EXPERIMENTAL DESIGN: CD137 expression on tumor-infiltrating lymphocytes was evaluated in a prospective cetuximab neoadjuvant trial, and CD137 stimulation was evaluated in a phase Ib trial, in combining agonistic urelumab with cetuximab. Flow cytometry and cytokine release assays using NK cells and DC were used in vitro, testing the addition of urelumab to cetuximab-activated NK, DC, and cross presentation to T cells. RESULTS: CD137 agonist mAb urelumab enhanced cetuximab-activated NK-cell survival, DC maturation, and tumor antigen cross-presentation. Urelumab boosted DC maturation markers, CD86 and HLA DR, and antigen-processing machinery (APM) components TAP1/2, leading to increased tumor antigen cross-presentation. In neoadjuvant cetuximab-treated patients with HNC, upregulation of CD137 by intratumoral, cetuximab-activated NK cells correlated with FcγRIIIa V/F polymorphism and predicted clinical response. Moreover, immune biomarker modulation was observed in an open label, phase Ib clinical trial, of patients with HNC treated with cetuximab plus urelumab. CONCLUSIONS: These results suggest a beneficial effect of combination immunotherapy using cetuximab and CD137 agonist in HNC. Clin Cancer Res; 23(3); 707-16. ©2016 AACR.
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Antígenos de Neoplasias/imunologia , Antineoplásicos Imunológicos/farmacologia , Carcinoma de Células Escamosas/imunologia , Cetuximab/farmacologia , Células Dendríticas/efeitos dos fármacos , Neoplasias de Cabeça e Pescoço/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Linfócitos do Interstício Tumoral/efeitos dos fármacos , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/imunologia , Ligante 4-1BB/imunologia , Anticorpos Monoclonais/farmacologia , Apresentação de Antígeno , Carcinoma de Células Escamosas/patologia , Linhagem Celular Tumoral , Citocinas/metabolismo , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Genótipo , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Células Matadoras Naturais/imunologia , Células Matadoras Naturais/metabolismo , Linfócitos/efeitos dos fármacos , Linfócitos/imunologia , Linfócitos do Interstício Tumoral/imunologia , Polimorfismo Genético , Receptor Cross-Talk/efeitos dos fármacos , Receptores de IgG/genética , Receptores de IgG/imunologia , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/agonistas , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/biossíntese , Membro 9 da Superfamília de Receptores de Fatores de Necrose Tumoral/genética , Regulação para Cima/efeitos dos fármacosRESUMO
PURPOSE OF REVIEW: This review examines the historical tumor progression genetic model of laryngeal carcinomas, from dysplasia to invasive carcinoma and the role of infiltrating immune and inflammatory cells as contributors to this process. RECENT FINDINGS: Classically, the genetic model of carcinogenesis describes overexpression of oncogenes and/or silencing of tumor suppressor genes which, when combined with exposure to environmental carcinogens over the course of time, results in damage to cellular DNA. Increasing evidence indicates that innate and adaptive immune mediators also play an important role in tumor progression of laryngeal carcinomas. Cellular mediators of immune suppression are often over represented in the tumor microenvironment and these cells release cytokines, which perpetuate immune suppression allowing for tumor immune evasion. SUMMARY: Future therapies targeting laryngeal malignancies should focus on a combined approach which targets both genetic variations and immune mediators.
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Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/imunologia , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/imunologia , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia , Progressão da Doença , HumanosRESUMO
BACKGROUND: Human papillomavirus type 16 (HPV16) E6 antibodies are a promising biomarker of oropharyngeal cancer (OPC); however, seropositivity among non-OPC cases is not well characterized. METHODS: Pre-treatment sera from 260 (38 OPC, 222 non-OPC) incident head and neck cancers diagnosed at the University of Pittsburgh between 2003 and 2006 were tested for HPV16 (L1,E1,E2,E4,E6,E7) and non-HPV16 E6 (HPV6,11,18,33) antibodies. Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven tumors was evaluated among tumors with known HPV status (n=25). RESULTS: 63.2% of OPC versus 27.5% of non-OPC cases were HPV16 seropositive; HPV16 E6 seroprevalence was 60.5% and 6.3% respectively, odds ratio 22.8 (95% confidence interval [CI] 9.8-53.1). Sensitivity and specificity of HPV16 E6 antibodies for HPV-driven OPC was 100% [95% CI: 50-100%; n=6] and 100% [95% CI: 60-100%, n=4] compared to 0% (n=2) and 0% (n=13) for non-OPC cases. CONCLUSIONS: HPV16 antibodies were significantly more common in OPC versus non-OPC cases, particularly HPV16 E6 antibodies.
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Papillomavirus Humano 16/imunologia , Proteínas Oncogênicas Virais/imunologia , Neoplasias de Cabeça e Pescoço , Humanos , Infecções por Papillomavirus/imunologia , Proteínas Repressoras/imunologia , Estudos SoroepidemiológicosRESUMO
Many cancer types, including head and neck cancers (HNC), express programmed death ligand 1 (PD-L1). Interaction between PD-L1 and its receptor, programmed death 1 (PD-1), inhibits the function of activated T cells and results in an immunosuppressive microenvironment, but the stimuli that induce PD-L1 expression are not well characterized. Interferon gamma (IFNγ) and the epidermal growth factor receptor (EGFR) utilize Janus kinase 2 (JAK2) as a common signaling node to transmit tumor cell-mediated extrinsic or intrinsic signals, respectively. In this study, we investigated the mechanism by which these factors upregulate PD-L1 expression in HNC cells in the context of JAK/STAT pathway activation, Th1 inflammation, and HPV status. We found that wild-type, overexpressed EGFR significantly correlated with JAK2 and PD-L1 expression in a large cohort of HNC specimens. Furthermore, PD-L1 expression was induced in an EGFR- and JAK2/STAT1-dependent manner, and specific JAK2 inhibition prevented PD-L1 upregulation in tumor cells and enhanced their immunogenicity. Collectively, our findings suggest a novel role for JAK2/STAT1 in EGFR-mediated immune evasion, and therapies targeting this signaling axis may be beneficial to block PD-L1 upregulation found in a large subset of HNC tumors.
Assuntos
Antígeno B7-H1/fisiologia , Receptores ErbB/fisiologia , Neoplasias de Cabeça e Pescoço/imunologia , Interferon gama/fisiologia , Janus Quinase 2/fisiologia , Fator de Transcrição STAT1/fisiologia , Antígeno B7-H1/análise , Linhagem Celular Tumoral , Fator de Crescimento Epidérmico/farmacologia , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Células Matadoras Naturais/imunologia , Papillomaviridae/isolamento & purificaçãoRESUMO
PURPOSE: EGF receptor (EGFR) is highly overexpressed on several cancers and two targeted anti-EGFR antibodies which differ by isotype are FDA-approved for clinical use. Cetuximab (IgG1 isotype) inhibits downstream signaling of EGFR and activates antitumor, cellular immune mechanisms. As panitumumab (IgG2 isotype) may inhibit downstream EGFR signaling similar to cetuximab, it might also induce adaptive immunity. EXPERIMENTAL DESIGN: We measured in vitro activation of cellular components of the innate and adaptive immune systems. We also studied the in vivo activation of components of the adaptive immune system in patient specimens from two recent clinical trials using cetuximab or panitumumab. RESULTS: Both monoclonal antibodies (mAb) primarily activate natural killer (NK) cells, although cetuximab is significantly more potent than panitumumab. Cetuximab-activated neutrophils mediate antibody-dependent cellular cytotoxicity (ADCC) against head and neck squamous cell carcinomas (HNSCC) tumor cells, and interestingly, this effect was FcγRIIa- and FcγRIIIa genotype-dependent. Panitumumab may activate monocytes through CD32 (FcγRIIa); however, monocytes activated by either mAb are not able to mediate ADCC. Cetuximab enhanced dendritic cell (DC) maturation to a greater extent than panitumumab, which was associated with improved tumor antigen cross-presentation by cetuximab compared with panitumumab. This correlated with increased EGFR-specific cytotoxic CD8+ T cells in patients treated with cetuximab compared with those treated with panitumumab. CONCLUSIONS: Although panitumumab effectively inhibits EGFR signaling to a similar extent as cetuximab, it is less effective at triggering antitumor, cellular immune mechanisms which may be crucial for effective therapy of HNSCC. Clin Cancer Res; 22(21); 5229-37. ©2016 AACR.
Assuntos
Anticorpos Monoclonais/imunologia , Anticorpos Monoclonais/uso terapêutico , Receptores ErbB/antagonistas & inibidores , Receptores ErbB/imunologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Imunidade Celular/imunologia , Linfócitos T CD8-Positivos/efeitos dos fármacos , Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Cetuximab/imunologia , Cetuximab/uso terapêutico , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/imunologia , Humanos , Imunidade Celular/efeitos dos fármacos , Imunoglobulina G/imunologia , Células Matadoras Naturais/efeitos dos fármacos , Células Matadoras Naturais/imunologia , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Panitumumabe , Receptores de IgG/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço , Linfócitos T Citotóxicos/efeitos dos fármacos , Linfócitos T Citotóxicos/imunologiaRESUMO
Cisplatin is a cytotoxic chemotherapeutic drug frequently used to treat many solid tumors, including head and neck squamous cell carcinoma (HNSCC). EGF receptor (EGFR) inhibitors have also shown efficacy as alternatives to cisplatin in some situations. However, large clinical trials have shown no added survival benefit from the use of these two drugs in combination. Possible explanations for this include overlapping downstream signaling cascades. Using in vitro studies, we tested the hypothesis that cisplatin and EGFR inhibitors rely on the activation of the tumor suppressor STAT1, characterized by its phosphorylation at serine (S727) or tyrosine (Y701) residues. Cisplatin consistently increased the levels of p-S727-STAT1, and STAT1 siRNA knockdown attenuated cisplatin-induced cell death. EGFR stimulation also activated p-S727-STAT1 and p-Y701-STAT1 in a subset of cell lines, whereas EGFR inhibitors alone decreased levels of p-S727-STAT1 and p-Y701-STAT1 in these cells. Contrary to our hypothesis, EGFR inhibitors added to cisplatin treatment caused variable effects among cell lines, with attenuation of p-S727-STAT1 and enhancement of cisplatin-induced cell death in some cells and minimal effect in other cells. Using HNSCC tumor specimens from a clinical trial of adjuvant cisplatin plus the anti-EGFR antibody panitumumab, higher intratumoral p-S727-STAT1 appeared to correlate with worse survival. Together, these results suggest that cisplatin-induced cell death is associated with STAT1 phosphorylation, and the addition of anti-EGFR therapy to cisplatin has variable effects on STAT1 and cell death in HNSCC.
Assuntos
Antineoplásicos/farmacologia , Carcinoma de Células Escamosas/metabolismo , Cisplatino/farmacologia , Receptores ErbB/metabolismo , Neoplasias de Cabeça e Pescoço/metabolismo , Fator de Transcrição STAT1/metabolismo , Anticorpos Monoclonais/administração & dosagem , Antineoplásicos/administração & dosagem , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/mortalidade , Carcinoma de Células Escamosas/patologia , Morte Celular/efeitos dos fármacos , Morte Celular/genética , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cisplatino/administração & dosagem , Fator de Crescimento Epidérmico/farmacologia , Receptores ErbB/antagonistas & inibidores , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Panitumumabe , Fosforilação , Prognóstico , RNA Interferente Pequeno/genética , Fator de Transcrição STAT1/agonistas , Fator de Transcrição STAT1/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Proteínas Quinases p38 Ativadas por Mitógeno/metabolismoRESUMO
OBJECTIVES: To analyze the outcomes of severe obstructive sleep apnea (OSA) in pediatric patients with Trisomy 21 compared with non-syndromic patients. METHODS: A retrospective chart review was performed for patients with a diagnosis of severe obstructive sleep apnea, (defined as, Apnea-Hypopnea index (AHI) of ≥ 10) in a tertiary children's hospital. Data were analyzed for subjective and objective outcomes along with perioperative care and health care utilization. Patients with Trisomy 21 were compared with non-syndromic patients. RESULTS: A total of 230 patients with severe OSA were included in the study. Eighteen of these patients had Trisomy 21. Adenotonsillectomy was the most common surgical intervention in both groups. There was no statistical difference in the preoperative AHI between groups. Post treatment AHI in the Trisomy 21 group changed from an average of 26.6 to an average of 11.6 as compared with 24.5 to 3.6 in the non-syndromic group. The average perioperative hospital stay was 3.8 days in Trisomy 21 group compared to 1.7 days for the non-syndromic group (p < 0.001, Mann-Whitney U test). Complete resolution was seen in 35% of the Trisomy 21 group versus 75% in the non-syndromic group. CONCLUSIONS: A majority of Trisomy 21 patients with severe OSA had residual symptoms following surgical intervention. There is also an increased risk of post-operative airway intervention and increased length of hospital stay in these patients.
Assuntos
Síndrome de Down/complicações , Apneia Obstrutiva do Sono/complicações , Apneia Obstrutiva do Sono/cirurgia , Adenoidectomia , Estudos de Casos e Controles , Criança , Feminino , Humanos , Tempo de Internação , Masculino , Polissonografia , Cuidados Pós-Operatórios , Estudos Retrospectivos , Índice de Gravidade de Doença , Tonsilectomia , Resultado do TratamentoRESUMO
The goal of this study was to characterize the molecular mechanisms underlying cetuximab-mediated upregulation of HLA class I antigen-processing machinery components in head and neck cancer (HNC) cells and to determine the clinical significance of these changes in cetuximab-treated HNC patients. Flow cytometry, signaling studies, and chromatin immunoprecipitation (ChIP) assays were performed using HNC cells treated with cetuximab alone or with Fcγ receptor (FcγR)-bearing lymphocytes to establish the mechanism of EGFR-dependent regulation of HLA APM expression. A prospective phase II clinical trial of neoadjuvant cetuximab was used to correlate HLA class I expression with clinical response in HNC patients. EGFR blockade triggered STAT1 activation and HLA upregulation, in a src homology-containing protein (SHP)-2-dependent fashion, more prominently in HLA-B/C than in HLA-A alleles. EGFR signaling blockade also enhanced IFNγ receptor 1 (IFNAR) expression, augmenting induction of HLA class I and TAP1/2 expression by IFNγ, which was abrogated in STAT1(-/-) cells. Cetuximab enhanced HNC cell recognition by EGFR853-861-specific CTLs, and notably enhanced surface presentation of a non-EGFR peptide (MAGE-3271-279). HLA class I upregulation was significantly associated with clinical response in cetuximab-treated HNC patients. EGFR induces HLA downregulation through SHP-2/STAT1 suppression. Reversal of HLA class I downregulation was more prominent in clinical responders to cetuximab therapy, supporting an important role for adaptive immunity in cetuximab antitumor activity. Abrogating EGFR-induced immune escape mechanisms and restoring STAT1 signaling to reverse HLA downregulation using cetuximab should be combined with strategies to enhance adaptive cellular immunity.