Your browser doesn't support javascript.
Mostrar: 20 | 50 | 100
Resultados 1 - 20 de 80
Filtrar
1.
Cancer Sci ; 111(6): 1943-1957, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32304268

RESUMO

Immune-checkpoint inhibitors improve the survival of head and neck squamous cell carcinoma (HNSCC) patients. Although recent studies have demonstrated that the tumor immune microenvironment (TIME) has critical roles in immunotherapy, the precise mechanisms involved are unclear. Therefore, further investigations of TIME are required for the improvement of immunotherapy. The frequency of effector regulatory T-cells (eTregs) and the expression of immune-checkpoint molecules (ICM) on eTregs and conventional T-cells (Tconvs) both in peripheral blood lymphocytes (PBL) and tumor-infiltrating lymphocytes (TIL) from HNSCC patients were analyzed by flow cytometry and their distributions were evaluated by multi-color immunofluorescence microscopy. High frequency eTreg infiltration into HNSCC tissues was observed and high expressions of CD25, FOXP3, stimulatory-ICM (4-1BB, ICOS, OX40 and GITR) and inhibitory-ICM (programmed cell death-1 [PD-1] and cytotoxic T-lymphocyte-associated protein-4 [CTLA-4]) were found on invasive eTregs. In contrast, the expression of stimulatory-ICM on Tconvs was low and the expression of inhibitory-ICM was high. In addition, ICM-ligands (programmed cell death-1 [PD-L1], galectin-9 and CEACAM-1) were frequently expressed on cancer cells. PD-L1 and galectin-9 were also expressed on macrophages. PD-1+ T-cells interacted with PD-L1+ cancer cells or PD-L1+ macrophages. This suggested that in TIL, eTregs are highly activated, but Tconvs are exhausted or inactivated by eTregs and immune-checkpoint systems, and ICM and eTregs are strongly involved in the creation of an immunosuppressive environment in HNSCC tissues. These suggested eTreg targeting drugs are expected to be a combination partner with immune-checkpoint inhibitors that will improve immunotherapy of HNSCC.


Assuntos
Neoplasias de Cabeça e Pescoço/imunologia , Linfócitos do Interstício Tumoral/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-Idade
2.
Cancer Immunol Immunother ; 69(7): 1205-1216, 2020 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-32146518

RESUMO

BACKGROUND: Multiple mechanisms of immunosuppression have been identified in the tumor microenvironment including regulatory B cells (Breg). Recently, we have shown that Breg suppress T cell function by production of adenosine (ADO). However, the autocrine effect of ADO on B cells and the role of Breg in head and neck cancer remains unclear. METHODS: Blood (n = 42) and tumor tissue (n = 39) of head and neck cancer patients and healthy donors (n = 60) were analyzed by FACS. The effect of ADO on phenotype, intracellular signaling pathways, Ca2+ influx and ADO production was analyzed in Breg and effector B cells (Beff) by FACS, luminescence and mass spectrometry. The blockage of the ADO receptor A2A was analyzed in a murine head and neck cancer model. RESULTS: ADO-producing Breg were found in tumor tissue and peripheral blood. ADO inhibited the intracellular Bruton's tyrosine kinase (BTK) and Ca2+ influx only in Beff. The inhibition of BTK by ibrutinib mimicked the effect of ADO, and ibrutinib reduced the production of ADO by downregulation of CD39 in vitro. The inhibition of ADO receptor A2A significantly reduced tumor mass and increased B cell infiltration, in vivo. CONCLUSION: Our data demonstrate the presence of a novel ADO-producing Breg population within the tumor microenvironment in mice and humans. A new model is proposed on how ADO-producing Breg can influence the function of Beff cells in healthy donors and cancer patients. Thus, the modulation of the ADO pathway in B cells may serve as a therapeutic approach for cancer patients.


Assuntos
Adenosina/metabolismo , Linfócitos B Reguladores/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Pirazóis/farmacologia , Pirimidinas/farmacologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Microambiente Tumoral/imunologia , Tirosina Quinase da Agamaglobulinemia/antagonistas & inibidores , Animais , Apoptose , Linfócitos B Reguladores/metabolismo , Estudos de Casos e Controles , Proliferação de Células , Neoplasias de Cabeça e Pescoço/metabolismo , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Masculino , Camundongos , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Células Tumorais Cultivadas , Ensaios Antitumorais Modelo de Xenoenxerto
3.
Am J Pathol ; 190(4): 900-915, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32035061

RESUMO

Tumor metastasis to the draining lymph nodes is critical in patient prognosis and is tightly regulated by molecular interactions mediated by lymphatic endothelial cells (LECs). The underlying mechanisms remain undefined in the head and neck squamous cell carcinomas (HNSCCs). Using HNSCC cells and LECs we determined the mechanisms mediating tumor-lymphatic cross talk. The effects of a pentacyclic triterpenoid, methyl 2-trifluoromethyl-3,11-dioxoolean-1,12-dien-30-oate (CF3DODA-Me), a potent anticancer agent, were studied on cancer-lymphatic interactions. In response to inflammation, LECs induced the chemokine (C-X-C motif) ligand 9/10/11 chemokines with a concomitant increase in the chemokine (C-X-C motif) receptor 3 (CXCR3) in tumor cells. CF3DODA-Me showed antiproliferative effects on tumor cells, altered cellular bioenergetics, suppressed matrix metalloproteinases and chemokine receptors, and the induction of CXCL11-CXCR3 axis and phosphatidylinositol 3-kinase/AKT pathways. Tumor cell migration to LECs was inhibited by blocking CXCL11 whereas recombinant CXCL11 significantly induced tumor migration, epithelial-to-mesenchymal transition, and matrix remodeling. Immunohistochemical analysis of HNSCC tumor arrays showed enhanced expression of CXCR3 and increased lymphatic vessel infiltration. Furthermore, The Cancer Genome Atlas RNA-sequencing data from HNSCC patients also showed a positive correlation between CXCR3 expression and lymphovascular invasion. Collectively, our data suggest a novel mechanism for cross talk between the LECs and HNSCC tumors through the CXCR3-CXCL11 axis and elucidate the role of the triterpenoid CF3DODA-Me in abrogating several of these tumor-promoting pathways.


Assuntos
Quimiocina CXCL11/metabolismo , Células Endoteliais/patologia , Neoplasias de Cabeça e Pescoço/patologia , Inflamação/patologia , Receptores CXCR3/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário , Antineoplásicos/farmacologia , Quimiocina CXCL11/genética , Células Endoteliais/efeitos dos fármacos , Células Endoteliais/imunologia , Células Endoteliais/metabolismo , Transição Epitelial-Mesenquimal , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/metabolismo , Humanos , Inflamação/tratamento farmacológico , Inflamação/imunologia , Inflamação/metabolismo , Metástase Linfática , Prognóstico , Receptores CXCR3/genética , Transdução de Sinais , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Triterpenos/farmacologia , Células Tumorais Cultivadas
4.
PLoS One ; 15(2): e0229089, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32092078

RESUMO

PURPOSE: The tumor-related myeloid derived suppressor cells (MDSCs), important immunosuppressive cells in tumor microenvironment, play an important role in the cancer progression. This study is aimed to investigate the crosstalk between MDSCs and oral squamous cell carcinoma (OSCC) cells and their role in the malignant progression of OSCC. METHODS: Immunochemistry (IHC) was used to investigate the expression of CD33 in 200 OSCC, 36 premalignant. CD33+ MDSCs were sorted and enriched via magnetic-activated cell sorting (MACS) from OSCC patients or health donor, and their phenotypes were identified by flow cytometry. With a co-culture system of MDSCs and OSCC, the effects of MDSCs on OSCC proliferation, apoptosis, migration invasion, epithelial-mesenchymal transition (EMT), and vasculogenic mimicry formation (VM) formation were assessed, respectively. Besides, peripheral blood mononuclear cells (PBMCs) from health donor were cultured with OSCC supernatant, the level of MDSCs and expressions of Arginase (Arg-1) and inducible nitric oxide synthase (iNOS) were measured. RESULTS: The number of MDSCs was increased in tumor tissues of OSCC patients, and was positively related to the T stage, pathological grade, lymph node metastasis and poor prognosis. Tumor-related MDSCs of the co-culture system promoted OSCC progression by contributing to cell proliferation, migration and invasion as well as inducing EMT and VM. In turn, OSCC cells had potential to induce MDSCs differentiation from PBMCs and increase the expression of Arg-1 and iNOS. CONCLUSION: These indicated that the crosstalk between MDSCs and tumor cells facilitated the malignant progression of OSCC cells and the immune suppressive properties of MDSCs, which may provide new insights into tumor treatment on targeting tumor-associated immunosuppressive cells.


Assuntos
Carcinogênese/imunologia , Neoplasias Bucais/patologia , Células Supressoras Mieloides/imunologia , Lesões Pré-Cancerosas/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/patologia , Comunicação Celular/imunologia , Células Cultivadas , Técnicas de Cocultura , Progressão da Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/sangue , Neoplasias Bucais/imunologia , Neoplasias Bucais/cirurgia , Estadiamento de Neoplasias , Lesões Pré-Cancerosas/imunologia , Cultura Primária de Células , Carcinoma de Células Escamosas de Cabeça e Pescoço/sangue , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Células Tumorais Cultivadas , Microambiente Tumoral/imunologia
5.
Immunity ; 52(1): 183-199.e9, 2020 01 14.
Artigo em Inglês | MEDLINE | ID: mdl-31924475

RESUMO

Head and neck squamous cell carcinoma (HNSCC) arises through exposure to environmental carcinogens or malignant transformation by human papillomavirus (HPV). Here, we assessed the transcriptional profiles of 131,224 single cells from peripheral and intra-tumoral immune populations from patients with HPV- and HPV+ HNSCC and healthy donors. Immune cells within tumors of HPV- and HPV+ HNSCC displayed a spectrum of transcriptional signatures, with helper CD4+ T cells and B cells being relatively divergent and CD8+ T cells and CD4+ regulatory T cells being relatively similar. Transcriptional results were contextualized through multispectral immunofluorescence analyses and evaluating putative cell-cell communication based on spatial proximity. These analyses defined a gene expression signature associated with CD4+ T follicular helper cells that is associated with longer progression-free survival in HNSCC patients. The datasets and analytical approaches herein provide a resource for the further study of the impact of immune cells on viral- and carcinogen-induced cancers.


Assuntos
Linfócitos B/imunologia , Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Auxiliares-Indutores/imunologia , Linfócitos T Reguladores/imunologia , Alphapapillomavirus/imunologia , Diferenciação Celular/imunologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Imunoterapia , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
6.
PLoS One ; 15(1): e0227261, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-31914141

RESUMO

The epidermal growth factor receptor inhibitor cetuximab is the only oncogene-targeted agent that has been FDA approved for the treatment of head and neck squamous cell carcinoma (HNSCC). Currently, there are no biomarkers used in the clinic to predict which HNSCC tumors will respond to cetuximab, and even in tumors that regress with treatment, acquired resistance occurs in the majority of cases. Though a number of mechanisms of acquired resistance to cetuximab have been identified in preclinical studies, no therapies targeting these resistance pathways have yet been effectively translated into the clinic. To address this unmet need, we examined the role of the cytokine interleukin 6 (IL-6) in acquired cetuximab resistance in preclinical models of HNSCC. We found that IL-6 secretion was increased in PE/CA-PJ49 cells that had acquired resistance to cetuximab compared to the parental cells from which they were derived. However, addition of exogenous IL-6 to parental cells did not promote cetuximab resistance, and inhibition of the IL-6 pathway did not restore cetuximab sensitivity in the cetuximab-resistant cells. Further examination of the IL-6 pathway revealed that expression of IL6R, which encodes a component of the IL-6 receptor, was decreased in cetuximab-resistant cells compared to parental cells, and that treatment of the cetuximab-resistant cells with exogenous IL-6 did not induce phosphorylation of signal transducer and activator of transcription 3, suggesting that the IL-6 pathway was functionally impaired in the cetuximab-resistant cells. These findings demonstrate that, even if IL-6 is increased in the context of cetuximab resistance, it is not necessarily required for maintenance of the resistant phenotype, and that targeting the IL-6 pathway may not restore sensitivity to cetuximab in cetuximab-refractory HNSCC.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/farmacologia , Resistencia a Medicamentos Antineoplásicos/imunologia , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Interleucina-6/metabolismo , Receptores de Interleucina-6/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/uso terapêutico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Carbazóis , Linhagem Celular Tumoral , Cetuximab/farmacologia , Cetuximab/uso terapêutico , Cisplatino/farmacologia , Cisplatino/uso terapêutico , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Ensaios de Seleção de Medicamentos Antitumorais , Receptores ErbB/antagonistas & inibidores , Técnicas de Silenciamento de Genes , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Interleucina-6/genética , Interleucina-6/imunologia , Fosforilação , RNA Interferente Pequeno/metabolismo , Receptores de Interleucina-6/antagonistas & inibidores , Receptores de Interleucina-6/genética , Receptores de Interleucina-6/imunologia , Proteínas Recombinantes/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
7.
Int J Cancer ; 146(4): 1152-1163, 2020 02 15.
Artigo em Inglês | MEDLINE | ID: mdl-31304591

RESUMO

Immune infiltrates have been increasingly recognized as robust prognostic factors for human cancer. Here, we developed and validated a seven-immune-feature-based prognostic score (7IFBPS) for patients with oral squamous cell carcinoma (OSCC) after curative resection. Fourteen immune features regarding detailed locations and densities of seven types of tumor-infiltrating immune cells (TIIs) were characterized in clinical samples from 269 eligible patients in three independent cohorts by immunohistochemistry coupled with digital quantitation. Optimal cutoff values for individual immune features were yielded using X-tile software. The 7IFBPS was constructed by Kaplan-Meier and Cox regression model in training cohort and verified in testing, validation and combined cohorts. Concordance index (C-index), receiver operating characteristics and calibration curves were employed to define the performance of 7IFBPS in prognostic prediction. High CD3 IM (invasive margin), CD3 CT (center of tumor), CD8 CT, CD45RO IM, CD45RO CT, FOXP3 IM and FOXP3 CT significantly associated with improved survival. The 7IFBPS score was calculated using the formula: 1.041 × CD3 IM + 1.24 × CD3 CT + 1.701 × CD8 CT + 1.127 × CD45RO IM + 1.348 × CD45RO CT + 1.089 × FOXP3 IM + 1.483 FOXP3 CT. High 7IFBPS significantly associated with improved survival in all cohorts and served as an independent prognostic predictor. The C-index of 7IFBPS for predicting survival was 0.668 (95% CI, 0.609-0.726). Calibration curves for survival probability showed good agreement between prediction by 7IFBPS and actual observation. Collectively, our findings established the 7IFBPS as a novel powerful prognostic classifier for resectable OSCC. It holds potentials to be incorporated into current prognostic regime to better patient stratification.


Assuntos
Biomarcadores Tumorais/análise , Mucosa Bucal/patologia , Neoplasias Bucais/cirurgia , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Feminino , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Invasividade Neoplásica/imunologia , Prognóstico , Curva ROC , Estudos Retrospectivos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade
8.
Int J Mol Sci ; 20(21)2019 Oct 30.
Artigo em Inglês | MEDLINE | ID: mdl-31671550

RESUMO

Head and neck squamous cell carcinoma (HNSCC) is often diagnosed at an advanced stage and has a dismal prognosis. Nearly 10 years after the approval of cetuximab, anti-PD1/PD-L1 checkpoint inhibitors are the first drugs that have shown any survival benefit for the treatment on platinum-refractory recurrent/metastatic (R/M) HNSCC. Furthermore, checkpoint inhibitors are better tolerated than chemotherapy. The state of the art in the treatment of R/M HNSCC is changing, thanks to improved results for checkpoint inhibitors. Results for these treatments are also awaited in curative settings and for locally advanced HNSCC. Unfortunately, the response rate of immunotherapy is low. Therefore, the identification of predictive biomarkers of response and resistance to anti-PD1/PD-L1 is a key point for better selecting patients that would benefit the most from immunotherapy. Furthermore, the combination of checkpoint inhibitors with various agents is being currently evaluated to improve the response rate, prolong response duration, and even increase the chances for a cure. In this review, we summarize the most important results regarding immune targeting agents for HNSCC, predictive biomarkers for resistance to immune therapies, and future perspectives.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Antígeno B7-H1/antagonistas & inibidores , Resistencia a Medicamentos Antineoplásicos , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Imunoterapia , Recidiva Local de Neoplasia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Resultado do Tratamento
9.
Int J Biol Markers ; 34(4): 398-405, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31674884

RESUMO

OBJECTIVE: To investigate the role of programmed death-1 (PD-1), programmed death-ligand 1 (PD-L1), and P16 in patients with head and neck squamous cell carcinoma (HNSCC). METHODS: A total of 95 paraffin-embedded samples of tumorous tissue of HNSCC were collected. Expression levels of PD-1, PD-L1, and P16 were determined by immunohistochemistry. RESULTS: A significantly higher proportion of PD-1 among patients infected with the human papillomavirus was found. PD-L1 expression is closely associated with the primary site of the tumor, postoperative recurrence, survival, PD-1 expression and P16 expression. Univariable analysis indicated that T stage, N stage, tumor node metastasis stage, tumor differentiation, and PD-L1 expression were all shown to be prognostic variables for overall survival in patients with HNSCC. In the multivariate analysis, only N stage (P = 0.010) and PD-L1 expression (P = 0.001) were found to be independent prognostic variables for overall survival. In addition, for disease recurrence, multivariate analysis showed that only PD-L1 expression was the associated independent risk factor. For the patients with negative PD-L1 expression, Kaplan-Meier analysis revealed that they had significantly worse outcomes in terms of overall survival (P = 0.001). Similarly, compared with the patients with positive PD-L1 expression, those with negative PD-L1 expression had a higher probability of recurrence (P = 0.026). CONCLUSIONS: The expression of PD-L1, PD-1, and P16 in HNSCC is significantly correlated. Human papillomavirus infection (P16 positive) is negatively related to postoperative recurrence. HNSCC patients with positive PD-L1/PD-1 expression tend to have better overall survival outcomes and lower probability of recurrence, providing more evidence for the PD-l-targeted immunotherapy of HNSCC.


Assuntos
Antígeno B7-H1/biossíntese , Neoplasias de Cabeça e Pescoço/imunologia , Receptor de Morte Celular Programada 1/biossíntese , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Antígeno B7-H1/imunologia , Feminino , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/mortalidade , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Prognóstico , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Análise de Sobrevida
10.
Cancer Immunol Immunother ; 68(12): 1935-1947, 2019 Dec.
Artigo em Inglês | MEDLINE | ID: mdl-31641795

RESUMO

BACKGROUND: Due to the strong tumoricidal activities of activated natural killer T (NKT) cells, invariant NKT cell-based immunotherapy has shown promising clinical efficacy. However, suppressive factors, such as regulatory T cells (Tregs), may be obstacles in the use of NKT cell-based cancer immunotherapy for advanced cancer patients. Here, we investigated the suppressive effects of Tregs on NKT cells and the underlying mechanisms with the aim to improve the antitumor activities of NKT cells. METHODS: Peripheral blood samples were obtained from healthy donors, patients with benign tumors, and patients with head and neck squamous cell carcinoma (HNSCC). NKT cells, induced with α-galactosylceramide (α-GalCer), and monocyte-derived dendritic cells (DCs) were co-cultured with naïve CD4+ T cell-derived Tregs to investigate the mechanism of the Treg suppressive effect on NKT cell cytotoxic function. The functions and phenotypes of NKT cells were evaluated with flow cytometry and cytometric bead array. RESULTS: Treg suppression on NKT cell function required cell-to-cell contact and was mediated via impaired DC maturation. NKT cells cultured under Treg-enriched conditions showed a decrease in CD4- NKT cell frequency, which exert strong tumoricidal responsiveness upon α-GalCer stimulation. The same results were observed in HNSCC patients with significantly increased effector Tregs. CONCLUSION: Tregs exert suppressive effects on NKT cell tumoricidal function by inducing more CD4- NKT cell anergy and less CD4+ NKT cell anergy. Both Treg depletion and NKT cell recovery from the anergy state may be important for improving the clinical efficacy of NKT cell-based immunotherapy in patients with advanced cancers.


Assuntos
Neoplasias de Cabeça e Pescoço/imunologia , Células T Matadoras Naturais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/imunologia , Idoso , Idoso de 80 Anos ou mais , Células Cultivadas , Anergia Clonal , Citotoxicidade Imunológica , Feminino , Humanos , Vigilância Imunológica , Imunossupressão , Masculino , Pessoa de Meia-Idade
11.
Zhonghua Zhong Liu Za Zhi ; 41(9): 641-647, 2019 Sep 23.
Artigo em Chinês | MEDLINE | ID: mdl-31550852

RESUMO

Over the past decades, although the clinical efficacy of advanced head and neck squamous cell carcinoma (HNSCC) has been moderately improved by the combination of cetuximab and chemotherapy, no remarkable treatment has emerged. The prognosis of HNSCC is still unsatisfied. With the deeper exploration of tumor immunological therapy, immunocheckpoint inhibitors such as monoclonal antibodies targeting on programmed cell death protein 1 (PD-1)/ cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) have shown appreciable anti-tumor effect on cancers such as melanoma and non-small cell lung cancer. Some successful clinical studies on HNSCC have also been reported, which provide a new opportunity for the improvement of HNSCC prognosis.Here we systemically review the progress of checkpoint inhibitors and its combination therapy in HNSCC, some immunotherapy efficacy-related biomarkers are also discussed.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Antígeno CTLA-4/antagonistas & inibidores , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia
12.
Braz Oral Res ; 33: e085, 2019 Aug 29.
Artigo em Inglês | MEDLINE | ID: mdl-31483051

RESUMO

The aim of this study was to evaluate the immunoexpression of human leukocyte antigen-DR (HLA-DR) in actinic cheilitis (AC) and lower lip squamous cell carcinoma (LLSCC), and to correlate the findings with clinical (tumor size/extent, regional lymph node metastasis, and clinical stage) and histopathological (grade of epithelial dysplasia and inflammatory infiltrate for AC and histopathological grade of malignancy for LLSCC) parameters. Twenty-four AC and 48 LLSCC cases (24 with regional nodal metastasis and 24 without regional nodal metastasis) were selected. The scores of immunopositive cells for HLA-DR in the epithelial component of the lesions were assessed and the results were analyzed statistically using the nonparametric Mann-Whitney test. Epithelial expression of HLA-DR was observed in only five (20.8%) cases of AC (two low-grade and three high-grade lesions), with a very low median score of immunopositivity. By contrast, expression of HLA-DR was found in most LLSCC (97.9%), with a relatively high median score of positive cells. The score of HLA-DR-positive cells tended to be higher in tumors with regional lymph node metastasis, tumors in advanced clinical stages, and low-grade tumors, but the difference was not statistically significant (p > 0.05). In addition, there was a tendency towards higher expression of HLA-DR in highly/moderately keratinized tumors, and tumors with little/moderate nuclear pleomorphism (p > 0.05). The results suggest a potential role of HLA-DR in lip carcinogenesis, particularly in the development and progression of LLSCC. The expression of this protein can be related to the degree of cell differentiation in these tumors.


Assuntos
Queilite/imunologia , Antígenos HLA-DR/imunologia , Neoplasias Labiais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinogênese/imunologia , Queilite/patologia , Feminino , Humanos , Inflamação/patologia , Neoplasias Labiais/patologia , Neoplasias Labiais/secundário , Metástase Linfática/patologia , Masculino , Pessoa de Meia-Idade , Gradação de Tumores , Estadiamento de Neoplasias , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/secundário
13.
Int J Cancer ; 145(12): 3436-3444, 2019 12 15.
Artigo em Inglês | MEDLINE | ID: mdl-31407331

RESUMO

There have been hints that nonviral cancer antigens are differentially expressed in human papillomavirus (HPV)-positive and HPV-negative head and neck squamous cell carcinoma (HNSCC). Antibody responses (AR) to cancer antigens may be used to indirectly determine cancer antigen expression in the tumor using a noninvasive and tissue-saving liquid biopsy. Here, we set out to characterize AR to a panel of nonviral cancer antigens in HPV-positive and HPV-negative HNSCC patients. A fluorescent microbead multiplex serology to 29 cancer antigens (16 cancer-testis antigens, 5 cancer-retina antigens and 8 oncogenes) and 29 HPV-antigens was performed in 382 HNSCC patients from five independent cohorts (153 HPV-positive and 209 HPV-negative). AR to any of the cancer antigens were found in 272/382 patients (72%). The ten most frequent AR were CT47, cTAGE5a, c-myc, LAGE-1, MAGE-A1, -A3, -A4, NY-ESO-1, SpanX-a1 and p53. AR to MAGE-A3, MAGE-A9 and p53 were found at significantly different prevalences by HPV status. An analysis of AR mean fluorescent intensity values uncovered remarkably different AR clusters by HPV status. To identify optimal antigen selections covering a maximum of patients with ≤10 AR, multiobjective optimization revealed distinct antigen selections by HPV status. We identified that AR to nonviral antigens differ by HPV status indicating differential antigen expression. Multiplex serology may be used to characterize antigen expression using serum or plasma as a tissue-sparing liquid biopsy. Cancer antigen panels should address the distinct antigen repertoire of HPV-positive and HPV-negative HNSCC.


Assuntos
Formação de Anticorpos/imunologia , Antígenos de Neoplasias/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Papillomaviridae/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/imunologia , Estudos de Coortes , Feminino , Humanos , Masculino , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Proteínas de Neoplasias/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Adulto Jovem
14.
Eur Arch Otorhinolaryngol ; 276(10): 2913-2922, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31312922

RESUMO

PURPOSE: The objective of this study was to investigate the prognostic role of three inflammatory markers: the neutrophil to lymphocyte ratio (NLR), the lymphocyte to monocyte ratio (LMR), and the platelet to lymphocyte ratio (PLR) as prognostic indicators in squamous cell carcinoma of the head and neck (HNSCC). METHODS: Patients with HNSCC treated with primary surgery, with or without adjuvant radiochemotherapy were enrolled. The preoperative NLR, LMR, and PLR were recorded. Confounding variables were also recorded: age, sex, BMI, comorbidities, performance status, AJCC T and N stage and HPV status. Endpoints were overall survival (OS) and event-free survival (EFS). Survival analysis was performed using Kaplan-Meier analysis, and multivariable analysis was performed using Cox proportional hazards regression. Survival models were evaluated using Harrell's concordance index (c-index). RESULTS: NLR (p = 0.2413), PLR (p = 0.1593), and LMR (p = 0.0552) were not significantly associated with OS in the multivariable analysis. With regard to EFS, low LMR (HR = 2.95, 95% CI 1.54-5.65, p = 0.001), high PLR (HR = 2.68, 95% CI 1.42-5.09, p = 0.003), and high NLR (HR = 3.37, 95% CI 1.7-6.69, p < 0.001) were associated with EFS. The multivariable c-index was highest for LMR (0.762), followed by NLR (0.761) and PLR (0.739). CONCLUSION: The LMR, PLR, and NLR were not associated with OS, but were associated with EFS in HNSCC. These markers are easily obtainable, and in the age of individualized patient care and precision medicine, they might represent further risk stratification tools for HNSCC patients.


Assuntos
Contagem de Células Sanguíneas/métodos , Plaquetas/patologia , Neoplasias de Cabeça e Pescoço/imunologia , Linfócitos/patologia , Monócitos/patologia , Neutrófilos/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Idoso , Feminino , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Imunidade Celular , Masculino , Pessoa de Meia-Idade , Prognóstico , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Análise de Sobrevida
15.
BMC Cancer ; 19(1): 715, 2019 Jul 19.
Artigo em Inglês | MEDLINE | ID: mdl-31324168

RESUMO

BACKGROUND: The rapid development of single-cell RNA sequencing (scRNA-seq) provides unprecedented opportunities to study the tumor ecosystem that involves a heterogeneous mixture of cell types. However, the majority of previous and current studies related to translational and molecular oncology have only focused on the bulk tumor and there is a wealth of gene expression data accumulated with matched clinical outcomes. RESULTS: In this paper, we introduce a scheme for characterizing cell compositions from bulk tumor gene expression by integrating signatures learned from scRNA-seq data. We derived the reference expression matrix to each cell type based on cell subpopulations identified in head and neck cancer dataset. Our results suggest that scRNA-Seq-derived reference matrix outperforms the existing gene panel and reference matrix with respect to distinguishing immune cell subtypes. CONCLUSIONS: Findings and resources created from this study enable future and secondary analysis of tumor RNA mixtures in head and neck cancer for a more accurate cellular deconvolution, and can facilitate the profiling of the immune infiltration in other solid tumors due to the expression homogeneity observed in immune cells.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , RNA-Seq/métodos , Análise de Célula Única/métodos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Linfócitos T Reguladores/imunologia , Bases de Dados Genéticas , Conjuntos de Dados como Assunto , Ecossistema , Genes Neoplásicos , Heterogeneidade Genética , Neoplasias de Cabeça e Pescoço/patologia , Humanos , RNA Citoplasmático Pequeno/genética , Software , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Transcriptoma , Microambiente Tumoral/genética , Microambiente Tumoral/imunologia
16.
Cancer Sci ; 110(9): 2783-2793, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31325403

RESUMO

Oral cancer, a subtype of head and neck cancer, is characterized by increased infiltrating regulatory T cells (Treg); however, the pathological significance of the increase in Tregs in disease prognosis and progression and their underlying mechanism remain unestablished. C-C motif chemokine ligand 22 (CCL22) has been implicated in the recruitment of Tregs. We used RT-qPCR to determine CCL22 mRNA expression in clinical specimens and cultured cells. Loss-of-function and gain-of-function studies were carried out to analyze the effects of CCL22 modulations on cell proliferation, migration, invasion, and tumorigenesis and the mechanism involved in the deregulation of CCL22. In oral cancer specimens, CCL22 mRNA was upregulated. The increase was not only associated with reduced disease-free survival but also strongly correlated with an increase in FOXP3 mRNA, a master regulator of Treg development and functions. Silencing CCL22 expression reduced cell proliferation, migration, and invasion, whereas ectopic overexpression showed opposite effects. Manipulation of CCL22 expression in cancer cells altered tumorigenesis in both immune-compromised and -competent mice, supporting both autonomous and non-autonomous actions of CCL22. Release of interleukin 1ß (IL-1ß) from cancer-associated fibroblasts (CAF) induces CCL22 mRNA expression in oral cancer cells by activating transcription factor nuclear factor kappa B (NF-κB). Our data support a model in which CAF-derived IL-1ß, CCL22, and its receptor CCR4 foster a protumor environment by promoting cell transformation and Treg infiltration. Intervention of the IL-1ß-CCL22-CCR4 signaling axis may offer a novel therapeutic strategy for oral cancer treatment.


Assuntos
Fibroblastos Associados a Câncer/metabolismo , Quimiocina CCL22/metabolismo , Interleucina-1beta/metabolismo , Neoplasias Bucais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Animais , Fibroblastos Associados a Câncer/imunologia , Linhagem Celular Tumoral , Movimento Celular/imunologia , Transformação Celular Neoplásica/imunologia , Transformação Celular Neoplásica/patologia , Quimiocina CCL22/genética , Intervalo Livre de Doença , Feminino , Seguimentos , Fatores de Transcrição Forkhead/metabolismo , Técnicas de Silenciamento de Genes , Humanos , Interleucina-1beta/genética , Masculino , Camundongos , Pessoa de Meia-Idade , Mucosa Bucal/patologia , Mucosa Bucal/cirurgia , Neoplasias Bucais/imunologia , Neoplasias Bucais/mortalidade , Neoplasias Bucais/cirurgia , Invasividade Neoplásica/imunologia , Invasividade Neoplásica/patologia , Prognóstico , RNA Interferente Pequeno/metabolismo , Receptores CCR4/metabolismo , Transdução de Sinais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Análise de Sobrevida , Linfócitos T Reguladores/imunologia , Linfócitos T Reguladores/metabolismo , Regulação para Cima , Ensaios Antitumorais Modelo de Xenoenxerto
17.
Am J Surg Pathol ; 43(10): 1392-1396, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31290758

RESUMO

Tumor-infiltrating lymphocytes (TILs) have shown a promising prognostic value in many epithelial cancers. We sought to assess the prognostic value of TILs in a multicenter cohort of early oral tongue squamous cell carcinoma (OTSCC). The percentage of TILs was assessed on the surgical resection slides stained with hematoxylin and eosin. The assessment of TILs was performed in the stromal compartment and in the intraepithelial compartment (at the invasive front and at the center of the tumor). We followed the method that was described recently by the International Immuno-Oncology Biomarker Working Group for the assessment of TILs. A total of 308 cases from the 5 Finnish university hospitals and from A.C. Camargo Cancer Center, São Paulo, Brazil, were included. We found a promising prognostic value for stromal TILs at the invasive front in the multivariable analysis with a hazard ratio of 2.61 (95% confidence interval [CI], 1.77-3.83; P<0.001) for overall survival, 1.99 (95% CI, 1.07-3.69; P=0.040) for disease-specific survival, and 1.94 (95% CI, 1.14-3.29; P=0.020) for disease-free survival. In conclusion, evaluation of TILs is simple and can aid in identifying the high-risk cases of early OTSCC. The method introduced by the International Immuno-Oncology Biomarker Working Group can be used for standardized determination of TILs in early OTSCC.


Assuntos
Linfócitos do Interstício Tumoral/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Neoplasias da Língua/patologia , Brasil , Intervalo Livre de Doença , Feminino , Finlândia , Humanos , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Medição de Risco , Fatores de Risco , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/mortalidade , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Fatores de Tempo , Neoplasias da Língua/imunologia , Neoplasias da Língua/mortalidade , Neoplasias da Língua/cirurgia , Microambiente Tumoral
18.
Expert Opin Biol Ther ; 19(9): 879-885, 2019 09.
Artigo em Inglês | MEDLINE | ID: mdl-31317798

RESUMO

Introduction: Groundbreaking progress in cancer immunotherapy in the recent years has revolutionized the field of oncology with unprecedented survival rates in multiple cancer types. Head and neck cancers comprise the sixth most common cancer type in the United States with estimated 14,620 deaths in 2019. Two checkpoint inhibitors, e.g. antibodies against programmed cell death protein 1 (PD-1), are currently FDA approved for second-line therapy of recurrent and/or metastatic head and neck squamous cell carcinomas (HNSCC). Pembrolizumab is one of the two approved anti-PD-1 antibodies and under active investigation of its role in managing HNSCCs. Areas covered: This review provides an in-depth discussion of pembrolizumab's structural features, pharmacokinetics, pharmacodynamics, efficacy data, toxicity profile, ongoing studies, and competing agents including the standard of care options in the context of treating HNSCCs. Expert opinion: Immune checkpoint inhibitor therapy is already an integral part of HNSCC management, especially in the recurrent and/or metastatic stage, and is preferable to conventional cytotoxic therapies due to a generally more favorable toxicity profile. Pembrolizumab's role in treating HNSCC is highly anticipated to expand over to other contexts such as definitive combination therapy and neoadjuvant therapy for locally advanced HNSCC.


Assuntos
Anticorpos Monoclonais Humanizados/uso terapêutico , Antineoplásicos Imunológicos/uso terapêutico , Neoplasias de Cabeça e Pescoço/tratamento farmacológico , Carcinoma de Células Escamosas de Cabeça e Pescoço/tratamento farmacológico , Animais , Neoplasias de Cabeça e Pescoço/imunologia , Humanos , Receptor de Morte Celular Programada 1/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia
19.
Anticancer Res ; 39(6): 3039-3046, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31177146

RESUMO

BACKGROUND/AIM: Programmed death-ligand 1 (PD-L1) expression in tumor cells is regulated by a close interrelation between tumor and stromal cells within the tumor microenvironment. Our aim was to evaluate the clinical and biological significance of PD-L1 expression in oral squamous cell carcinoma (OSCC). MATERIALS AND METHODS: PD-L1, cluster of differentiation (CD)4, CD8, and forkhead box P3 (FOXP3) expression in tumor tissues obtained from 77 patients with OSCC was evaluated by immunohistochemical staining, and then analyzed for associations with clinical and biological factors. RESULTS: Among the clinicopathological factors tested, only vascular invasion showed a trend toward lower PD-L1 expression (p=0.05). Metabolic tumor volume (MTV), and total lesion glycolysis (TLG) significantly positively correlated with PD-L1 expression (MTV, p=0.04; TLG, p=0.03). In patients with OSCC with high PD-L1 expression, those whose tumors had abundant infiltrating CD4+ T-cells showed a longer progression-free survival than those with low CD4+ T-cell infiltration (p=0.0452). CONCLUSION: As regulation of PD-L1 expression is complex, its evaluation combined with other markers may be useful to determine clinical applications of PD-L1 expression.


Assuntos
Antígeno B7-H1/análise , Biomarcadores Tumorais/análise , Neoplasias Bucais/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Microambiente Tumoral , Adulto , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos/imunologia , Feminino , Glicólise , Humanos , Imuno-Histoquímica , Linfócitos do Interstício Tumoral/imunologia , Masculino , Pessoa de Meia-Idade , Neoplasias Bucais/diagnóstico por imagem , Neoplasias Bucais/metabolismo , Neoplasias Bucais/cirurgia , Tomografia por Emissão de Pósitrons , Intervalo Livre de Progressão , Carcinoma de Células Escamosas de Cabeça e Pescoço/diagnóstico por imagem , Carcinoma de Células Escamosas de Cabeça e Pescoço/metabolismo , Carcinoma de Células Escamosas de Cabeça e Pescoço/cirurgia , Fatores de Tempo , Carga Tumoral
20.
Cancer Immunol Immunother ; 68(7): 1133-1141, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31139925

RESUMO

Advanced oral squamous cell carcinomas (OSCC) have limited therapeutic options. Although immune therapies are emerging as a potentially effective alternative or adjunct to chemotherapies, the therapeutic efficacy of combination immune chemotherapies has yet to be determined. Using a 4-nitroquinolone-N-oxide (4NQO) orthotopic model of OSCC in immunocompetent mice, we evaluated the therapeutic efficacy of single- and combined-agent treatment with a poly-epitope tumor peptide vaccine, cisplatin and/or an A2AR inhibitor, ZM241385. The monotherapies or their combinations resulted in a partial inhibition of tumor growth and, in some cases, a significant but transient upregulation of systemic anti-tumor CD8+ T cell responses. These responses eroded in the face of expanding immunoregulatory cell populations at later stages of tumor progression. Our findings support the need for the further development of combinatorial therapeutic approaches that could more effectively silence dominant immune inhibitory pathways operating in OSCC and provide novel, more beneficial treatment options for this tumor.


Assuntos
Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Vacinas Anticâncer/uso terapêutico , Imunoterapia/métodos , Neoplasias Bucais/terapia , Neoplasias Experimentais/terapia , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , 4-Nitroquinolina-1-Óxido/toxicidade , Animais , Cisplatino/uso terapêutico , Terapia Combinada/métodos , Feminino , Camundongos , Camundongos Endogâmicos C57BL , Neoplasias Bucais/induzido quimicamente , Neoplasias Bucais/imunologia , Neoplasias Bucais/patologia , Neoplasias Experimentais/induzido quimicamente , Neoplasias Experimentais/imunologia , Neoplasias Experimentais/patologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/induzido quimicamente , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/patologia , Resultado do Tratamento , Triazinas/uso terapêutico , Triazóis/uso terapêutico , Vacinas de Subunidades/uso terapêutico
SELEÇÃO DE REFERÊNCIAS
DETALHE DA PESQUISA