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1.
Cancer Sci ; 112(4): 1402-1416, 2021 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-33529452

RESUMO

Human papillomavirus (HPV) is an important etiological factor of head and neck squamous cell carcinoma (HNSCC). HPV+ HNSCC patients usually have a better prognosis, which probably results from the higher infiltration of B lymphocytes. This study was purposed to detect the infiltration of B lymphocyte subsets and the correlation between B lymphocyte subsets and the prognosis in HPV-related HNSCC. In this study, 124 HPV+ and 513 HPV- HNSCC samples were obtained from the Gene Expression Omnibus (GEO) database and The Cancer Genome Atlas (TCGA) database for transcriptomic analysis. Infiltration of B lymphocytes subsets was detected with 7 HPV+ HNSCC and 13 HPV- HNSCC tissues through immunohistochemistry and immunofluorescence. One HPV- HNSCC sample was detected with single-cell sequencing for chemokine analysis. In the results, the infiltration of plasma cells (CD19+ CD38+ ) and memory B cells (MS4A1+ CD27+ ) was higher in HPV+ HNSCC samples. High infiltration of plasma cells and memory B cells was related to a better prognosis. High density of B lymphocytes was positively correlated with high CXCL13 production mainly from CD4+ T lymphocytes in HNSCC. These results indicated that a high density of plasma cells and memory B cells could predict excellent prognosis. CD4+ T lymphocytes might affect B lymphocytes and their subsets through the CXCL13/CXCR5 axis in HNSCC.


Assuntos
Alphapapillomavirus/imunologia , Linfócitos B/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Idoso , Linfócitos T CD4-Positivos/imunologia , Carcinoma de Células Escamosas/virologia , Quimiocina CXCL13/imunologia , Feminino , Neoplasias de Cabeça e Pescoço/virologia , Humanos , Masculino , Pessoa de Meia-Idade , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Prognóstico , Receptores CXCR5/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia
2.
Int J Mol Sci ; 22(3)2021 Feb 02.
Artigo em Inglês | MEDLINE | ID: mdl-33540711

RESUMO

The macroscopic and microscopic anatomy of the oral cavity is complex and unique in the human body. Soft-tissue structures are in close interaction with mineralized bone, but also dentine, cementum and enamel of our teeth. These are exposed to intense mechanical and chemical stress as well as to dense microbiologic colonization. Teeth are susceptible to damage, most commonly to caries, where microorganisms from the oral cavity degrade the mineralized tissues of enamel and dentine and invade the soft connective tissue at the core, the dental pulp. However, the pulp is well-equipped to sense and fend off bacteria and their products and mounts various and intricate defense mechanisms. The front rank is formed by a layer of odontoblasts, which line the pulp chamber towards the dentine. These highly specialized cells not only form mineralized tissue but exert important functions as barrier cells. They recognize pathogens early in the process, secrete antibacterial compounds and neutralize bacterial toxins, initiate the immune response and alert other key players of the host defense. As bacteria get closer to the pulp, additional cell types of the pulp, including fibroblasts, stem and immune cells, but also vascular and neuronal networks, contribute with a variety of distinct defense mechanisms, and inflammatory response mechanisms are critical for tissue homeostasis. Still, without therapeutic intervention, a deep carious lesion may lead to tissue necrosis, which allows bacteria to populate the root canal system and invade the periradicular bone via the apical foramen at the root tip. The periodontal tissues and alveolar bone react to the insult with an inflammatory response, most commonly by the formation of an apical granuloma. Healing can occur after pathogen removal, which is achieved by disinfection and obturation of the pulp space by root canal treatment. This review highlights the various mechanisms of pathogen recognition and defense of dental pulp cells and periradicular tissues, explains the different cell types involved in the immune response and discusses the mechanisms of healing and repair, pointing out the close links between inflammation and regeneration as well as between inflammation and potential malignant transformation.


Assuntos
Polpa Dentária/patologia , Periodontite Periapical/patologia , Tecido Periapical/patologia , Pulpite/patologia , Animais , Antígenos de Neoplasias/imunologia , Carcinogênese/imunologia , Carcinoma de Células Escamosas/etiologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/fisiopatologia , Quimiocinas/metabolismo , Proteínas do Sistema Complemento/metabolismo , Cárie Dentária/fisiopatologia , Polpa Dentária/microbiologia , Dentina/irrigação sanguínea , Dentina/inervação , Dentina/metabolismo , Fibroblastos/imunologia , Fibroblastos/metabolismo , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/fisiologia , Células-Tronco Mesenquimais/fisiologia , Neoplasias Bucais/etiologia , Neoplasias Bucais/imunologia , Neoplasias Bucais/fisiopatologia , Rede Nervosa/fisiologia , Neuropeptídeos/metabolismo , Óxido Nítrico/fisiologia , Odontoblastos/fisiologia , Granuloma Periapical/etiologia , Granuloma Periapical/patologia , Tecido Periapical/microbiologia , Cisto Radicular/etiologia , Cisto Radicular/fisiopatologia
3.
Medicine (Baltimore) ; 100(2): e24073, 2021 Jan 15.
Artigo em Inglês | MEDLINE | ID: mdl-33466167

RESUMO

ABSTRACT: Lung squamous carcinoma (LUSC) is a common subtype of lung cancer with limited available therapy and is thus associated with poor survival. Immune infiltrating cells and immune-related genes (IRGs) play a key role in the clinical outcomes of LUSC. In the present study, we aimed to develop a potential immunogenomic prognostic signature for patients with LUSC. The transcriptional profiles of 501 LUSC samples from The Cancer Genome Atlas (TCGA) and 2498 IRGs from the ImmPort database were used to develop the signature by Cox regression analysis. Ten differentially expressed and survival-associated IRGs were used to develop the risk signature, which could serve as an independent prognostic and predictive factor for patients with LUSC. Furthermore, this risk signature correlated with overall survival and clinical features, including age, in patients with LUSC. In addition, we identified 25 transcription factors that may regulate 15 survival-associated IRGs, using a regulatory network. Collectively, this immunogenomic signature could be a robust prognostic tool for patients with LUSC and holds great promise as individualized immunotherapy for LUSC.


Assuntos
Biomarcadores Tumorais/genética , Carcinoma de Células Escamosas/genética , Fenômenos Imunogenéticos/genética , Neoplasias Pulmonares/genética , Transcriptoma/genética , Carcinoma de Células Escamosas/imunologia , Bases de Dados Genéticas , Humanos , Neoplasias Pulmonares/imunologia , Nomogramas , Valor Preditivo dos Testes , Prognóstico , Modelos de Riscos Proporcionais , Análise de Sobrevida
4.
Bull Cancer ; 108(1): 80-89, 2021 Jan.
Artigo em Francês | MEDLINE | ID: mdl-33423780

RESUMO

Despite its status as a rare disease, the incidence of the squamous cell carcinoma of the anus (SCCA) is surging, especially in its metastatic form. In addition, the prognosis of initially localized diseases has not substantially changed since the 1970s with a recurrence rate of between 25-40 % after the chemoradiotherapy. The updated data from 115 patients included in the Epitopes-HPV01 and Epitopes-HPV02 trials, confirm the modified regimen of DCF (mDCF) as the treatment of choice for patients with advanced SCCA given the rate of sustained remissions and complete molecular responses observed. The carboplatin-paclitaxel regimen may be considered as an option for patients with contraindication to cisplatin or 5-FU. In chemo-refractory patients, the efficacy of anti-PD-1/PD-L1 in monotherapy is limited and only brings benefit to 10-20 % of patients, and its use cannot be generalized in the absence of an association potentiating its effectiveness. In order to better understand the immunological parameters associated with advanced SCCA, an analysis of peripheral immune responses was carried out in the Epitopes-HPV01 and 02 trials. It demonstrated the key role of CD4 Th1 specific responses of telomerase and M-MDSC as main prognostic factors for the therapeutic efficacy of DCF. Numerous combination trials are currently underway or will soon begin in localized SCCA, as well as in the first and second-line in the advanced stage. Finally, the detection of circulating tumor DNA of HPV oncoprotein E6 and E7 (HPVtc), especially by the "digital droplet PCR" technique, is highly sensitive and specific, and can be used in daily practice.


Assuntos
Neoplasias do Ânus/terapia , Carcinoma de Células Escamosas/terapia , Alphapapillomavirus/genética , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêutico , Neoplasias do Ânus/imunologia , Neoplasias do Ânus/patologia , Neoplasias do Ânus/virologia , Carboplatina/administração & dosagem , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/virologia , Cisplatino/efeitos adversos , Ensaios Clínicos como Assunto , Contraindicações de Medicamentos , DNA Viral/análise , Fluoruracila/efeitos adversos , Humanos , Imunidade Celular , Recidiva Local de Neoplasia , Paclitaxel/administração & dosagem , Telomerase/imunologia
5.
Int J Mol Sci ; 22(1)2020 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-33375467

RESUMO

Vulvar cancer (VC) is a rare neoplasm, usually arising in postmenopausal women, although human papilloma virus (HPV)-associated VC usually develop in younger women. Incidences of VCs are rising in many countries. Surgery is the cornerstone of early-stage VC management, whereas therapies for advanced VC are multimodal and not standardized, combining chemotherapy and radiotherapy to avoid exenterative surgery. Randomized controlled trials (RCTs) are scarce due to the rarity of the disease and prognosis has not improved. Hence, new therapies are needed to improve the outcomes of these patients. In recent years, improved knowledge regarding the crosstalk between neoplastic and tumor cells has allowed researchers to develop a novel therapeutic approach exploiting these molecular interactions. Both the innate and adaptive immune systems play a key role in anti-tumor immunesurveillance. Immune checkpoint inhibitors (ICIs) have demonstrated efficacy in multiple tumor types, improving survival rates and disease outcomes. In some gynecologic cancers (e.g., cervical cancer), many studies are showing promising results and a growing interest is emerging about the potential use of ICIs in VC. The aim of this manuscript is to summarize the latest developments in the field of VC immunoncology, to present the role of state-of-the-art ICIs in VC management and to discuss new potential immunotherapeutic approaches.


Assuntos
Carcinoma de Células Escamosas/imunologia , Imiquimode/farmacologia , Imunoterapia/métodos , Melanoma/imunologia , Tumores Neuroendócrinos/imunologia , Doença de Paget Extramamária/imunologia , Neoplasias Vulvares/imunologia , Adjuvantes Imunológicos/farmacologia , Adjuvantes Imunológicos/uso terapêutico , Alphapapillomavirus/imunologia , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/patologia , Feminino , Humanos , Imiquimode/uso terapêutico , Melanoma/tratamento farmacológico , Melanoma/patologia , Tumores Neuroendócrinos/tratamento farmacológico , Tumores Neuroendócrinos/patologia , Doença de Paget Extramamária/tratamento farmacológico , Doença de Paget Extramamária/patologia , Prognóstico , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/patologia , Neoplasias Vulvares/virologia
6.
Rev. ADM ; 77(6): 287-294, nov.-dic. 2020. ilus, tab
Artigo em Espanhol | LILACS | ID: biblio-1150870

RESUMO

Introducción: El carcinoma oral de células escamosas (COCE) es una neoplasia epitelial maligna que se presenta frecuentemente entre la quinta y sexta década de la vida. Su compleja patogénesis incluye el proceso de angiogénesis y la regulación del microambiente tumoral como mecanismos de progresión tumoral. Objetivo: Determinar la relación entre las variables clínicas e histológicas del COCE con la inmunoexpresión de VEGF, FGF-1, FGFR-1, TGFB-1, TGFBR-II y CD105. Material y métodos: Nueve casos de COCE; tres bien (BD), tres moderado (MD) y tres pobremente diferenciados (PD) obtenidos del Departamento de Patología y Medicina Bucal, División de Estudios de Postgrado e Investigación. Se aplicó la técnica de inmunohistoquímica por peroxidasa para identificar la expresión de VEGF, FGF-1, FGFR- 1, TGFB-1, TGFBR-II y CD105. El análisis de inmunoexpresión se realizó con el programa ImageJ. Se aplicó la prueba de Kruskal-Wallis y correlación de Spearman (p < 0.05). Resultados: La inmunoexpresión de VEGF fue mayor en los COCE PD, FGFR-1 fue positivo en los BD, mientras que FGF, TGFB-1 y TGFBR-II fueron negativos. El análisis de microdensidad vascular (MVD) indicó mayor número de vasos CD105 positivos en los carcinomas BD, seguidos de los PD y MD. Conclusión: Considerando los resultados obtenidos podemos concluir que la angiogénesis es un fenómeno constante independiente del grado de diferenciación que durante el proceso de transformación de una neoplasia requerirá la formación de vasos sanguíneos y que este proceso puede ser modulado por factores de crecimiento tales como los analizados en este trabajo (AU)


Introduction: Oral squamous cell carcinoma (OSCC) is a malignant epithelial neoplasm that frequently occurs between the fifth and sixth decade of life. Its complex pathogenesis includes the angiogenesis process and the regulation of the tumor microenvironment as mechanisms of tumor progression. Objective: To determine the relationship between the clinical and histological variables of OSCC with the immunoexpression of VEGF, FGF-1, FGFR-1, TGFB- 1, TGFBR-II and CD105. Material and methods: Nine cases of OSCC; three well (WD), three moderate (MD) and three poorly differentiated (PD) obtained from the Oral Medicine and Pathology Department, Division of Graduate Studies and Research. The peroxidase immunohistochemistry technique was performed to identify the expression of VEGF, FGF-1, FGFR-1, TGFB-1, TGFBR-II and CD105. The immunoexpression analysis was performed with the ImageJ software. The Kruskal-Wallis and Spearman correlation test were performed (p < 0.05). Results: VEGF immunoexpression was higher in PD OSCC, while FGFR-1 was predominantly positive in WD; FGF, TGFB-1 and TGFBR-II were negative. Vascular microdensity analysis (MVD) indicated a greater number of CD105 positive vessels in WD carcinomas, followed by PD and MD. Conclusion: Considering the results obtained, we can conclude that angiogenesis is a constant phenomenon independent of the degree of differentiation; that during the transformation process of a neoplasm it will require the formation of blood vessels and that this process can be modulated by growth factors such as those analyzed in this work (AU)


Assuntos
Humanos , Masculino , Feminino , Adulto , Pessoa de Meia-Idade , Idoso , Carcinoma de Células Escamosas/imunologia , Fator 1 de Crescimento de Fibroblastos , Fator A de Crescimento do Endotélio Vascular , Vasos Sanguíneos , Imuno-Histoquímica , Análise Estatística , Técnicas Histológicas , Peptídeos e Proteínas de Sinalização Intercelular , Receptor Tipo 1 de Fator de Crescimento de Fibroblastos , Endoglina , México
7.
J Hematol Oncol ; 13(1): 174, 2020 12 11.
Artigo em Inglês | MEDLINE | ID: mdl-33308264

RESUMO

Immunotherapy has been a new standard for recurrent/metastatic head and neck cancers (R/M HNC). One of the prominent characteristics of cancer immunotherapy is the induction of immune memory followed by endured treatment response. However, whether and how a treatment delay would impact on the efficacy of immunotherapy has not been well determined. During the outbreak of COVID-19, a number of cancer patients in Wuhan, the epicenter of the pandemic in China, had experienced long-lasting city lockdown and delay of immunotherapies. Here, we retrospectively analyzed 24 HNC patients treated with immune checkpoint inhibitors in our cancer institute prior to the outbreak of COVID-19 who were re-evaluated after the restoration of regular medical care. Of these 24 patients, 10 patients had achieved complete response (CR) or partial response (PR), 12 patients had achieved stable disease (SD), and 2 patients had received just one cycle treatment without efficacy evaluation before treatment delay. The median delay was 3.75 months (range 1.73-8.17 months). Re-evaluation after treatment delay revealed that ten patients (10/10) who achieved CR or PR, two patients (2/2) who received just one cycle treatment without efficacy evaluation and seven patients (7/12) who achieved SD before outbreak of COVID-19 maintained tumor response after treatment delay. Among the rest five patients who had achieved SD, four patients were re-evaluated as progressive disease (PD) due to treatment delay and one patient died after treatment interruption without re-evaluation. Our results from a small cohort of R/M HNC patients showed that treatment delay of three to four months might have mild, if any, impact on the efficacy of immunotherapy for patients with controlled disease.


Assuntos
/fisiopatologia , Carcinoma de Células Escamosas/terapia , Neoplasias de Cabeça e Pescoço/terapia , Imunoterapia/métodos , Adulto , Idoso , /virologia , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , China , Feminino , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/patologia , Humanos , Masculino , Pessoa de Meia-Idade , Metástase Neoplásica , Recidiva Local de Neoplasia , Pandemias , Estudos Retrospectivos , Tempo para o Tratamento , Resultado do Tratamento
8.
J Cancer Res Ther ; 16(3): 445-451, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32719249

RESUMO

Introduction: Several studies regarding tumor-stroma ratio (TSR) in colorectal, esophageal, breast, endometrial, and cervical carcinomas have been done in the past with significant results. Objectives: The objectives of this study were to (1) study and grade TSR in buccal mucosa and tongue squamous cell carcinoma (SCC), (2) grade inflammatory cell infiltrate surrounding the tumor, and (3) correlate the above two parameters with tumor grade, lymph node metastasis, lymphovascular invasion (LVI), and perineural invasion (PNI). Materials and Methods: Totally, 25 patients of buccal SCC and 16 cases of tongue SCC were included in the study. TSR was assessed visually on the hematoxylin and eosin-stained tissue sections by two independent observers. Cases were categorized into two groups: One with high TSR >50% (stroma poor) and the other with low TSR <50% as the stroma-rich group. TSR was correlated with tumor size, lymph node metastasis, inflammatory cell infiltrate, LVI, and PNI. Data were analyzed by the Statistical Package for the Social Sciences version 16.0 (Chicago, IL, USA) for Windows. The Chi-square and Fischer's exact tests were applied in the analysis of categorical variable. Results and Conclusion: SCC of buccal mucosa showed a significant correlation between TSR and size of the tumor (P = 0.001). We found that smaller the tumor size ≤2 cm (Stage T1), lesser the TSR, and size >2 cm was found to be associated with higher TSR. Hence, higher TSR (stroma poor) was associated with an adverse pathological characteristic, i.e., advanced T significantly. There was no significant correlation between TSR and inflammatory infiltrate with grade of the tumor, lymph node metastasis, LVI, and PNI. In 16 cases of SCC of the tongue; no correlation was observed between TSR and inflammatory infiltrate with tumor size, grade of the tumor, lymph node metastasis, LVI, and PNI. TSR has been studied in various malignancies (mostly adenocarcinomas) including laryngeal SCCs; however, it has never been studied on oral SCCs.


Assuntos
Carcinoma de Células Escamosas/patologia , Mucosa Bucal/patologia , Neoplasias Bucais/patologia , Células Estromais/patologia , Neoplasias da Língua/patologia , Língua/patologia , Adulto , Idoso , Carcinoma de Células Escamosas/imunologia , Feminino , Humanos , Metástase Linfática , Masculino , Pessoa de Meia-Idade , Mucosa Bucal/imunologia , Neoplasias Bucais/imunologia , Gradação de Tumores , Estadiamento de Neoplasias , Estudos Retrospectivos , Fatores de Risco , Células Estromais/imunologia , Língua/imunologia , Neoplasias da Língua/imunologia , Adulto Jovem
9.
Am J Surg Pathol ; 44(9): 1184-1191, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32496434

RESUMO

Tumor cell expression of major histocompatibility complex (MHC) class I is required for antigen presentation and adaptive immune recognition. Absent or diminished MHC class I expression is thought to contribute to immunotherapeutic resistance in some epithelial tumors but has not been previously studied in cervical and vulvar carcinoma. Given that anti-programmed cell death 1 (PD-1) checkpoint inhibition is deployed for programmed cell death ligand 1 (PD-L1)-positive recurrent and metastatic cervical squamous carcinomas, identifying tumors with loss of MHC class I is of clinical interest to optimize the selection of immunotherapeutic candidates. Immunohistochemistry for PD-L1 and MHC class I combined A, B, and C heavy chains (MHC class I) was assessed in 58 human papillomavirus-associated cervical and vulvar lesions, including 27 squamous intraepithelial lesions (SILs) and 31 invasive squamous cell carcinoma (SCC). Although 84% of SCC and 22% of SIL were PD-L1-positive, 35.5% (11/31) of SCC and 18.5% (5/27) of SIL also showed clonal or complete loss of MHC class I. Loss of MHC class I expression was more common in PD-L1-positive (10/26, 38%) versus PD-L1-negative SCC (1/5, 20%). In summary, over one third of human papillomavirus-associated cervical and vulvar SCC show clonal or complete loss of MHC class I expression, including many PD-L1-positive cases. This suggests that the efficacy of checkpoint inhibitors targeting the PD-1/PD-L1 axis may be limited in a subset of cervical and vulvar squamous neoplasms due to an impaired ability to engage with the adaptive immune system related to loss of MHC class I expression.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/virologia , Resistencia a Medicamentos Antineoplásicos , Antígenos de Histocompatibilidade Classe I/imunologia , Papillomaviridae/patogenicidade , Infecções por Papillomavirus/virologia , Lesões Intraepiteliais Escamosas Cervicais/virologia , Neoplasias do Colo do Útero/virologia , Neoplasias Vulvares/virologia , Antineoplásicos Imunológicos/efeitos adversos , Antígeno B7-H1/antagonistas & inibidores , Antígeno B7-H1/imunologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Regulação para Baixo , Feminino , Interações Hospedeiro-Patógeno , Humanos , Papillomaviridae/imunologia , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/patologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/imunologia , Estudos Retrospectivos , Lesões Intraepiteliais Escamosas Cervicais/tratamento farmacológico , Lesões Intraepiteliais Escamosas Cervicais/imunologia , Lesões Intraepiteliais Escamosas Cervicais/patologia , Neoplasias do Colo do Útero/tratamento farmacológico , Neoplasias do Colo do Útero/imunologia , Neoplasias do Colo do Útero/patologia , Neoplasias Vulvares/tratamento farmacológico , Neoplasias Vulvares/imunologia , Neoplasias Vulvares/patologia
10.
Nat Cell Biol ; 22(7): 758-766, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32483388

RESUMO

Cancer-associated fibroblasts (CAFs) perform diverse roles and can modulate therapy responses1. The inflammatory environment within tumours also influences responses to many therapies, including the efficacy of oncolytic viruses2; however, the role of CAFs in this context remains unclear. Furthermore, little is known about the cell signalling triggered by heterotypic cancer cell-fibroblast contacts and about what activates fibroblasts to express inflammatory mediators1,3. Here, we show that direct contact between cancer cells and CAFs triggers the expression of a wide range of inflammatory modulators by fibroblasts. This is initiated following transcytosis of cytoplasm from cancer cells into fibroblasts, leading to the activation of STING and IRF3-mediated expression of interferon-ß1 and other cytokines. Interferon-ß1 then drives interferon-stimulated transcriptional programs in both cancer cells and stromal fibroblasts and ultimately undermines the efficacy of oncolytic viruses, both in vitro and in vivo. Further, targeting IRF3 solely in stromal fibroblasts restores oncolytic herpes simplex virus function.


Assuntos
Fibroblastos Associados a Câncer/imunologia , Instabilidade Genômica , Fator Regulador 3 de Interferon/metabolismo , Proteínas de Membrana/metabolismo , Terapia Viral Oncolítica , Neoplasias Cutâneas/imunologia , Células Estromais/imunologia , Adulto , Animais , Fibroblastos Associados a Câncer/metabolismo , Fibroblastos Associados a Câncer/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Carcinoma de Células Escamosas/terapia , Células Cultivadas , Citocinas , Interações Hospedeiro-Patógeno , Humanos , Fator Regulador 3 de Interferon/genética , Masculino , Proteínas de Membrana/genética , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Vírus Oncolíticos/genética , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Neoplasias Cutâneas/terapia , Células Estromais/metabolismo , Células Estromais/patologia , Ensaios Antitumorais Modelo de Xenoenxerto
11.
J Cancer Res Clin Oncol ; 146(8): 1971-1978, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32447484

RESUMO

PURPOSE: Interleukin-10 (IL-10) is an immunoregulatory cytokine and its cervical and serum concentrations have been associated with a poor prognosis of cervical cancer. The rs1800872 polymorphism (c.-592C>A) in the promotor region of the IL-10 gene affects the production and expression of IL-10 and thus is able to determine the immune response profile in the cervix. Therefore, the aim of this work is to state the association between IL-10 c.-592C>A polymorphism and cervical cancer. METHODS: Genomic DNA was extracted from patient's peripheral blood and tumor biopsy. Socio-demographic, sexual behavior and reproductive characteristics data were collected using a questionnaire. RESULTS: Co-dominant model in logistic binary regression adjusted for confounders, showed that patients presenting with C/A genotype had 2.15 times more chances for developing cervical cancer (OR 2.15; CI95% 1.02-4.56). The dominant model, C/A + A/A, was also independently associated with 2.71 times more chances for cervical cancer development when compared to control patients (OR 2.71; CI95% 1.05-4.47). CONCLUSION: Our study analyses show the association between cervical cancer and IL-10 c.-592C>A polymorphism, demonstrating that the allele A presence was independently associated with higher risks of cervical cancer development.


Assuntos
Interleucina-10/genética , Neoplasias do Colo do Útero/genética , Adenocarcinoma/sangue , Adenocarcinoma/genética , Adenocarcinoma/imunologia , Adulto , Carcinoma de Células Escamosas/sangue , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Estudos de Casos e Controles , DNA/sangue , DNA/genética , Feminino , Genótipo , Humanos , Interleucina-10/biossíntese , Interleucina-10/imunologia , Polimorfismo de Nucleotídeo Único , Regiões Promotoras Genéticas , Neoplasias do Colo do Útero/sangue , Neoplasias do Colo do Útero/imunologia
12.
Eur J Cancer ; 132: 150-158, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32371248

RESUMO

BACKGROUND: We evaluated programmed death ligand 1 (PD-L1) expression and efficacy of PD-1/PD-L1 inhibitors in patients with pulmonary pleomorphic carcinoma (PC). METHODS: We created two cohorts of patients diagnosed with pulmonary PC from 2016 to 2019, PD-L1 expression and programmed death 1 (PD-1)/PD-L1 inhibitor efficacy cohorts. The PD-L1 expression cohort included all patients evaluated for PD-L1 expression, irrespective of PD-1/PD-L1 inhibitor therapy. High PD-L1 expression was defined as ≥50% positive tumour cells (TC) for 22C3, ≥25% for SP263 or ≥10%/5% TC/immune cell (IC) for SP142. The PD-1/PD-L1 efficacy cohort included patients treated with PD-1/PD-L1 inhibitors, irrespective of PD-L1 tests. RESULTS: One hundred twenty-five of 175 patients diagnosed with pulmonary PCs were included in the PD-L1 expression cohort. Among them, 112 patients (89.6%) had PD-L1-positive (≥1%) tumours and 100 (80.0%) had tumours with high PD-L1 expression. A total of 49 patients were included in the efficacy cohort: 40 received pembrolizumab, 7 nivolumab and 2 atezolizumab. The objective response rate was 49.0%, with a median progression-free survival (PFS) of 7.2 months and a median overall survival of 22.2 months. In the efficacy cohort, high PD-L1 expression (n = 41) was associated with longer PFS (median: 7.2 versus 1.5 months, hazard ratio [HR]: 0.53 [0.22-1.29], p = 0.16) and overall survival (median: 22.2 versus 3.5, HR: 0.21 [0.08-0.57], p = 0.001) than low/negative/unknown PD-L1 expression (n = 8). CONCLUSION: PD-1/PD-L1 inhibitors show outstanding efficacy for pulmonary PCs, and this is possibly attributable to high PD-L1 expression in these tumours.


Assuntos
Adenocarcinoma de Pulmão/mortalidade , Antineoplásicos Imunológicos/uso terapêutico , Antígeno B7-H1/antagonistas & inibidores , Carcinoma Pulmonar de Células não Pequenas/mortalidade , Carcinoma de Células Escamosas/mortalidade , Neoplasias Pulmonares/mortalidade , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Adenocarcinoma de Pulmão/tratamento farmacológico , Adenocarcinoma de Pulmão/imunologia , Adenocarcinoma de Pulmão/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma Pulmonar de Células não Pequenas/tratamento farmacológico , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Feminino , Seguimentos , Humanos , Neoplasias Pulmonares/tratamento farmacológico , Neoplasias Pulmonares/imunologia , Neoplasias Pulmonares/patologia , Masculino , Pessoa de Meia-Idade , Prognóstico , Estudos Retrospectivos , Taxa de Sobrevida
13.
Mol Carcinog ; 59(7): 745-753, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32301180

RESUMO

Despite a decline in the incidence of squamous cell carcinomas (SCCs) over the past 20 years, their survival rate has remained nearly the same, indicating that treatment options have not improved relative to other cancer types. Immunotherapies have a high potential for a sustained effect in SCC patients, but their response rate is low. Here, we review the suppressive role of transforming growth factor-beta (TGFß) on the antitumor immune response in SCC and present its potential as a therapeutic target in combination with the current range of immunotherapies available for SCC patients. We conclude that SCCs are an optimal cancer type to study the effectiveness of TGFß inhibition due to the prevalence of dysregulated TGFß signaling in them.


Assuntos
Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/metabolismo , Inflamação/imunologia , Inflamação/metabolismo , Fator de Crescimento Transformador beta/imunologia , Fator de Crescimento Transformador beta/metabolismo , Animais , Humanos , Imunoterapia/métodos , Transdução de Sinais/imunologia
15.
PLoS One ; 15(4): e0231227, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32251447

RESUMO

Growing evidence suggests that the efficacy of immunotherapy in non-small cell lung cancers (NSCLCs) is associated with the immune microenvironment within the tumor. We aimed to explore radiologic phenotyping using a radiomics approach to assess the immune microenvironment in NSCLC. Two independent NSCLC cohorts (training and test sets) were included. Single-sample gene set enrichment analysis was used to determine the tumor microenvironment, where type 1 helper T (Th1) cells, type 2 helper T (Th2) cells, and cytotoxic T cells were the targets for prediction with computed tomographic (CT) radiomic features. Multiple algorithms were in the modeling followed by final model selection. The training dataset comprised 89 NSCLCs and the test set included 60 cases of lung squamous cell carcinoma and adenocarcinoma. A total of 239 CT radiomic features were used. A linear discriminant analysis model was selected for the final model of Th2 cell group prediction. The area under the curve value of the final model on the test set was 0.684. Predictors of the linear discriminant analysis model were skewness (total and outer pixels), kurtosis, variance (subsampled from delta [subtraction inner pixels from outer pixels]), and informational measure of correlation. The performances of radiomics on test set of Th1 and cytotoxic T cell were not accurate enough to be predictable. A radiomics approach can be used to interrogate an entire tumor in a noninvasive manner and provide added diagnostic value to identify the immune microenvironment of NSCLC, in particular, Th2 cell signatures.


Assuntos
Adenocarcinoma/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Neoplasias Pulmonares/imunologia , Microambiente Tumoral/imunologia , Idoso , Algoritmos , Conjuntos de Dados como Assunto , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Radiografia , Linfócitos T Citotóxicos/imunologia , Tomografia Computadorizada por Raios X/métodos
16.
J Surg Res ; 251: 321-328, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32200323

RESUMO

BACKGROUND: The aim of this study was to evaluate the association between the expression of programmed death ligand-1 (PD-L1) and clinical outcomes in patients with surgically resected esophageal squamous cell carcinoma (ESCC). MATERIALS AND METHODS: We included 76 patients with primary ESCC who underwent surgical resection between January 2009 and December 2014 at National Defense Medical College Hospital. Using the tumor tissues, we evaluated PD-L1 expression in tumor cells and stromal reactive lymphocytes via immunohistochemistry. Furthermore, the relationship between PD-L1 expression and the clinicopathological status of patients with ESCC was investigated. RESULTS: PD-L1 expression in tumor cells was detected in 39.5% of the patients. In addition, 51.3% of the patients had PD-L1-positive stromal reactive lymphocytes and exhibited significantly longer overall survival than those with lack of PD-L1 expression in stromal reactive lymphocytes (median survival time, 56.0 versus 27.3 mo; log-rank test, P = 0.04). Patients with lack of PD-L1 expression in both tumor cells and stromal reactive lymphocytes showed worse overall survival than those with the PD-L1-positive expression in tumor cells and/or stromal reactive lymphocytes (P = 0.02). CONCLUSIONS: PD-L1-positive expression in stromal reactive lymphocytes, rather than in tumor cells, is associated with a longer survival in patients with ESCC.


Assuntos
Antígeno B7-H1/metabolismo , Carcinoma de Células Escamosas/metabolismo , Neoplasias Esofágicas/metabolismo , Adulto , Idoso , Idoso de 80 Anos ou mais , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/mortalidade , Neoplasias Esofágicas/imunologia , Neoplasias Esofágicas/mortalidade , Feminino , Humanos , Japão/epidemiologia , Linfócitos/metabolismo , Masculino , Pessoa de Meia-Idade , Estudos Retrospectivos
17.
Oncogene ; 39(17): 3541-3554, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-32115573

RESUMO

Molecular characteristics of carcinoma arising from mature cystic teratoma of the ovary (MCT) remain unclear due to its rarity. We analyzed RNA-sequencing data of 2322 pan-cancer [1378 squamous cell carcinomas (SCC), 6 adenosquamous carcinomas (ASC), and 938 adenocarcinomas (AC)] including six carcinomas arising from MCT (four SCCs, one ASC, and one AC). Hierarchical clustering and principal component analysis showed that gene expression profiles of carcinomas arising from MCT were different between each histological type and that gene expression profiles of SCCs arising MCT (MCT-SCCs) was apparently similar to those of lung SCCs. By epidermis-associated pathways activity based on gene set enrichment analysis, 1030 SCCs were divided into two groups: epidermis-signature high (head and neck, esophagus, and skin) and low (cervix, lung, and MCT). In addition to pan-SCC transcriptome analysis, cytokeratin profiling based on immunohistochemistry in the independent samples of 21 MCT-SCCs clarified that MCT-SCC dominantly expressed CK18, suggesting the origin of MCT-SCC was columnar epithelium. Subsequently, we investigated differentially expressed genes in MCT-SCCs compared with different SCCs and identified XCL1 was specifically overexpressed in MCT-SCCs. Through immunohistochemistry analysis, we identified XCL1 expression on tumor cells in 13/24 (54%) of MCT-SCCs but not in MCTs. XCL1 expression was also significantly associated with the number of tumor-infiltrating CD8-positive T cells and PD-L1 expression on tumor cells. XCL1 produced by tumor cells may induce PD1/PD-L1 interaction and dysfunction of CD8-positive T cells in tumor microenvironment. XCL1 expression may be a novel biomarker for malignant transformation of MCT into SCC and a biomarker candidate for therapeutic response to an anti-PD1/PD-L1 therapy.


Assuntos
Antígeno B7-H1 , Linfócitos T CD8-Positivos , Carcinoma de Células Escamosas , Quimiocinas C , Regulação Neoplásica da Expressão Gênica/imunologia , Linfócitos do Interstício Tumoral , Proteínas de Neoplasias , Neoplasias Ovarianas , Teratoma , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/imunologia , Carcinoma de Células Escamosas/patologia , Quimiocinas C/genética , Quimiocinas C/imunologia , Feminino , Humanos , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/patologia , Proteínas de Neoplasias/genética , Proteínas de Neoplasias/imunologia , Neoplasias Ovarianas/genética , Neoplasias Ovarianas/imunologia , Neoplasias Ovarianas/patologia , Teratoma/genética , Teratoma/imunologia , Teratoma/patologia
18.
BMC Cancer ; 20(1): 229, 2020 Mar 17.
Artigo em Inglês | MEDLINE | ID: mdl-32183719

RESUMO

BACKGROUND: Although checkpoint blockades have become widely used, the immunological impact in cancer patients, especially those with oral cavity squamous cell carcinoma (OCSCC), has not been well studied. METHODS: The present study assessed the immunological impact of anti-PD-1 (nivolumab) treatment in 10 patients with OCSCC. This involved phenotypic analyses of peripheral blood T-cell subpopulations and their expression of immune mediators prior to and following nivolumab treatment. The focus was on immunological effects of treatment without regard to possible clinical responses. RESULTS: Nivolumab caused a decline in the frequency of blood CD4+ cells but did not affect their expression of IFN-γ. However, nivolumab increased the proportion of CD4+ cells expressing the Treg-supporting factor Foxp3. Nivolumab treatment caused an increase in the proportion of CD8+ cells. While their expression of granzyme B increased, it did not attain significance. Analyses of CD8+ cell subpopulations showed nivolumab caused an increase in levels of unconventional CD8dimCD3+ T-cells. It also caused an increase in expression of granzyme B by these unconventional T-cells as well as by the conventional CD8hiCD3+ cells. The CD8hiCD3+ subpopulation also had a near-significant increase in IFN-γ expression. Treatment with nivolumab had no effect on the levels of the NK containing CD8dimCD3- subpopulation of cells or their expression of IFN-γ or granzyme B. CONCLUSIONS: These results show nivolumab causes opposing effects on CD4+ and CD8+ cell populations, with CD4+ cell levels declining but increasing the proportion of Treg cells, and unconventional CD8+ T-cell levels increasing with increased expression of immune mediators by CD8+ T-cell subpopulations.


Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/imunologia , Neoplasias Bucais/tratamento farmacológico , Neoplasias Bucais/imunologia , Nivolumabe/uso terapêutico , Idoso , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Humanos , Imunoterapia , Masculino , Pessoa de Meia-Idade , Linfócitos T Reguladores/imunologia
19.
Biochem Biophys Res Commun ; 526(1): 218-224, 2020 05 21.
Artigo em Inglês | MEDLINE | ID: mdl-32204917

RESUMO

The immunological, and especially T cell, status of the tumor microenvironment affects tumor development and the efficacy of cancer treatment. To devise suitable combination therapies based on the results of murine tumor models, a more realistic orthotopic model is required. In this study, we generated a murine model of tongue squamous cell carcinoma (SCC), in which the tumor-immune cell interactions were recapitulated, and examined tumor- and T-cell status compared to a skin-transplanted SCC model by multiplex immunofluorescence staining for epidermal growth factor receptor, CD31, CD8, CD4, and Foxp3. Administration of SCCVII cells did not induce undesirable tissue damage or inflammation. In tongue SCC, abundant T-cell infiltration was observed at the tumor margin, but not in the core. Tongue SCC predominantly showed CD8+ T or Foxp3+ regulatory T cell (Treg)-infiltration. In contrast, skin-transplanted SCC showed abundant infiltration of T cells in the whole tumor area, which was dominated by Tregs. An orthotopic tongue SCC model showed differences in tumor and T-cell status compared to the skin-transplanted SCC model. Our tongue SCC model may enhance understanding of tumor-host interactions and enable evaluation of therapeutic efficacy.


Assuntos
Linfócitos T CD8-Positivos/imunologia , Carcinoma de Células Escamosas/imunologia , Linfócitos do Interstício Tumoral/imunologia , Neoplasias Cutâneas/imunologia , Linfócitos T Reguladores/imunologia , Neoplasias da Língua/imunologia , Animais , Linhagem Celular Tumoral , Modelos Animais de Doenças , Feminino , Contagem de Linfócitos , Camundongos
20.
J Pathol ; 251(2): 147-159, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32222046

RESUMO

Direct quantification of exhausted T cells in human cancer is lacking, and its predictive value for checkpoint-based treatment remains poorly investigated. We sought to systematically characterize the pan-cancer landscape and molecular hallmarks of T-cell dysfunction for the purpose of precision immunotherapy. Here, we defined a transcriptional signature for T-cell exhaustion through analyzing differential gene expression between PD-1-high and PD-1-negative CD8+ T lymphocytes from primary non-small cell lung cancer (NSCLC), followed by positive correlation tests with PDCD1 in TCGA lung carcinomas. A 78-gene signature for exhausted CD8+ T cells (GET) was identified and validated to reflect dysfunctional immune state spanning different species and disease models. We discovered that GET estimation significantly correlated with intratumoral immune cytolytic activity (CYT) and T-cell-inflamed gene expression profile (GEP) across 30 solid tumor types. Miscellaneous tumor-intrinsic and -extrinsic properties, in particular leukocyte proportions, genomic abnormalities, specific mutational signatures, and signaling pathways, were notably associated with GET levels. Furthermore, higher GET expression predicted an increased likelihood of clinical response to immune checkpoint inhibitors. These findings highlight the interrelation between T-cell exhaustion and immune cytolytic activity at the pan-cancer scale. The resulting inflamed tumor microenvironment may further crosstalk with other molecular and clinicopathological factors, which should be properly considered during immunotherapy biomarker development. © 2020 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.


Assuntos
Adenocarcinoma de Pulmão/imunologia , Linfócitos T CD8-Positivos/imunologia , Carcinoma Pulmonar de Células não Pequenas/imunologia , Carcinoma de Células Escamosas/imunologia , Citotoxicidade Imunológica , Neoplasias Pulmonares/imunologia , Linfócitos do Interstício Tumoral/imunologia , Microambiente Tumoral , Adenocarcinoma de Pulmão/genética , Adenocarcinoma de Pulmão/patologia , Linfócitos T CD8-Positivos/patologia , Carcinoma Pulmonar de Células não Pequenas/genética , Carcinoma Pulmonar de Células não Pequenas/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Humanos , Neoplasias Pulmonares/genética , Neoplasias Pulmonares/patologia , Linfócitos do Interstício Tumoral/patologia , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Transcriptoma
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