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Photothermal therapy is favored by cancer researchers due to its advantages such as controllable initiation, direct killing and immune promotion. However, the low enrichment efficiency of photosensitizer in tumor site and the limited effect of single use limits the further development of photothermal therapy. Herein, a photo-responsive multifunctional nanosystem was designed for cancer therapy, in which myeloid-derived suppressor cell (MDSC) membrane vesicle encapsulated decitabine-loaded black phosphorous (BP) nanosheets (BP@ Decitabine @MDSCs, named BDM). The BDM demonstrated excellent biosafety and biochemical characteristics, providing a suitable microenvironment for cancer cell killing. First, the BDM achieves the ability to be highly enriched at tumor sites by inheriting the ability of MDSCs to actively target tumor microenvironment. And then, BP nanosheets achieves hyperthermia and induces mitochondrial damage by its photothermal and photodynamic properties, which enhancing anti-tumor immunity mediated by immunogenic cell death (ICD). Meanwhile, intra-tumoral release of decitabine induced G2/M cell cycle arrest, further promoting tumor cell apoptosis. In vivo, the BMD showed significant inhibition of tumor growth with down-regulation of PCNA expression and increased expression of high mobility group B1 (HMGB1), calreticulin (CRT) and caspase 3. Flow cytometry revealed significantly decreased infiltration of MDSCs and M2-macrophages along with an increased proportion of CD4+, CD8+ T cells as well as CD103+ DCs, suggesting a potentiated anti-tumor immune response. In summary, BDM realizes photothermal therapy/photodynamic therapy synergized chemotherapy for cancer.
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Células Supresoras de Origen Mieloide , Neoplasias , Fotoquimioterapia , Biomimética , Linfocitos T CD8-positivos , Decitabina/farmacología , Terapia Fototérmica , Neoplasias/tratamiento farmacológicoRESUMEN
OBJECTIVE: Ferroptosis has been defined as a novel form of regulated cell death characterized by iron-dependent lipid peroxidation. Manganese has been used to induce ferroptosis in cancer cells recently. This study aims to investigate whether manganese can induce ferroptosis in oral squamous cell carcinoma (OSCC) and the underlying biological mechanisms. MATERIALS AND METHODS: Cancer cells with or without manganese treatment were analyzed by RNA-sequencing to identify ferroptosis-related genes. Next, the activation of YAP/TAZ/ACSL4-ferroptosis signaling pathway was detected. Bioinformatic analysis and immunofluorescence assay were used to explore the phase separation of YAP/TAZ. Finally, specimens of OSCC patients were applied to analyze the clinical significance of YAP/TAZ/ACSL4. RESULTS: RNA-sequencing analysis showed the ferroptosis-related genes and YAP/TAZ were upregulated after manganese treatment. The results of immunofluorescence, ELISA, western blotting, etc. further confirmed that manganese-induced ferroptosis depends on YAP/TAZ/ACSL4 signaling pathway. Moreover, the activation of ACSL4 was achieved by YAP/TAZ phase separation. The survival analysis in OSCC specimen suggested that the higher level of YAP/TAZ-ACSL4 axis expression indicates longer survival. CONCLUSIONS: Manganese induces YAP/TAZ phase separation and subsequent ACSL4 activation via YAP/TAZ nuclear translocation, which facilitates ferroptosis of OSCC. Then YAP/TAZ-ACSL4 axis can be used as a potential prognostic predictor of OSCC patients.
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Myeloid-derived suppressor cells (MDSCs) are one of the tumor-infiltrating immune cell population, which play a powerful role in inhibiting anti-tumor immune response. Our previous studies have shown that STAT3 blockade can decrease the number of MDSCs in tumor microenvironment. However, it is unclear for the molecular mechanism of down-regulation MDSCs with STAT3 inhibitor. In this study, we first detected and analyzed the expression of p-STAT3, CD33, CD14, CD39 and CD73 via oral squamous cell carcinoma (OSCC) tissue array. We found that p-STAT3 was positively correlated with CD14, CD33, CD39, and CD73 in OSCC patient specimens. Then we found STAT3 blockade with S3I-201 reduced the expression of CD39/CD73 and the synthesis of adenosine, as well as inhibiting monocytes to MDSCs differentiation in vitro. Furthermore, we found that S3I-201 displayed prominent anti-tumor efficacy in C3H/He OSCC mouse model via inhibiting CD39/CD73-adenosine signal pathway and decreasing MDSCs. These results suggest that STAT3 signal can induce the differentiation of monocytes into MDSCs in tumor microenvironment depending on CD39/CD73-adenosine signal pathway and STAT3 blockade is a promising therapeutic strategy for OSCC.
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Carcinoma de Células Escamosas , Neoplasias de Cabeza y Cuello , Neoplasias de la Boca , Células Supresoras de Origen Mieloide , Animales , Ratones , Adenosina/farmacología , Adenosina/metabolismo , Carcinoma de Células Escamosas/metabolismo , Diferenciación Celular , Neoplasias de Cabeza y Cuello/metabolismo , Ratones Endogámicos C3H , Monocitos/metabolismo , Neoplasias de la Boca/patología , Transducción de Señal , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Microambiente Tumoral , 5'-Nucleotidasa/metabolismoRESUMEN
Accumulated evidence indicates that immune cell populations play pivotal roles in the process of tumor initiation, progression, recurrence, metastasis, and immune escape. Ferroptosis is a form of regulating cell death in the nexus between metabolism, redox biology, and human health. Ferroptosis is considered as a vital important event in HNSCC, but the underling mechanism of regulating immune cell populations remains poorly understood. Our tissue microarray study showed that patients with high expression of GPX4 were related to poor survival. Moreover, the expression of GPX4 has been negatively associated with immunogenic cell death-related protein calreticulin in HNSCC tissue cohort. Further, RSL3 was used to induce ferroptosis in HNSCC xenograft of C3H/He mouse. We found that the occurrence of ferroptosis had significantly reduced the number of myeloid-derived suppressor cells (MDSCs) and tumor-associated M2-like macrophages (M2 TAMs) in tumor microenvironment. Meanwhile, the tumor-infiltrating CD4+ and CD8+ T cells were increased. And the calreticulin and HMGB1 may be potential candidate proteins improving the immunosuppressive tumor microenvironment. Taken together, our project suggests that ferroptosis can promote anti-tumor immune response by reversing immunosuppressive microenvironment, indicating that ferroptosis inducer is a promising therapeutic strategy in HNSCC.
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Ferroptosis , Neoplasias de Cabeza y Cuello , Humanos , Ratones , Animales , Carcinoma de Células Escamosas de Cabeza y Cuello , Calreticulina , Linfocitos T CD8-positivos , Ratones Endogámicos C3H , Inmunidad , Microambiente TumoralRESUMEN
Oral disease, as a class of diseases with very high morbidity, brings great physical and mental damage to people worldwide. The increasing burden and strain on individuals and society make oral diseases an urgent global health problem. Since the treatment of almost all oral diseases relies on materials, the rapid development of advanced materials and technologies has also promoted innovations in the treatment methods and strategies of oral diseases. In this review, we systematically summarized the application strategies in advanced materials and technologies for oral diseases according to the etiology of the diseases and the comparison of new and old materials. Finally, the challenges and directions of future development for advanced materials and technologies in the treatment of oral diseases were refined. This review will guide the fundamental research and clinical translation of oral diseases for practitioners of oral medicine.
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OBJECTIVES: Our study elucidates the prognostic role of cluster of differentiation (CD) 24 expression in oral squamous cell carcinoma (OSCC) and determines whether targeting CD24 enhances the anti-tumor immune response by inhibiting tumor-associated macrophages (TAMs). MATERIALS AND METHODS: The expression of CD24 and CD68 was analyzed immunohistochemically via tissue microarrays constructed using 56 cohorts of patients with OSCC and 20 control specimens. Further, CD24 was inhibited in an allograft squamous cell carcinoma (SCC) related mouse model with CD24mAb to determine the tumor volume and weight. Changes in immune cells such as TAMs and T cells in the tumor microenvironment (TME) were analyzed by Flow cytometry. The expression of CD4, CD8, and Ki67 was analyzed via immunohistochemistry. The inhibition of CD24 was confirmed by Western blot and immunohistochemistry. RESULTS: CD24 was overexpressed in OSCC. High expression of CD24 indicated poor survival in patients with OSCC (p = 0.0334). CD24 expression was significantly correlated with CD68 (p = 0.0424). The inhibition of CD24 delayed tumor growth in vivo. A decrease in TAMs number and an increase in T cell number were confirmed, while the ability of tumor proliferation was impaired. CONCLUSION: Targeting CD24 could enhance anti-tumor immune response by inhibiting TAMs.
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Herein, we report that genetically programmable fusion cellular vesicles (Fus-CVs) displaying high-affinity SIRPα variants and PD-1 can activate potent antitumor immunity through both innate and adaptive immune effectors. Dual-blockade of CD47 and PD-L1 with Fus-CVs significantly increases the phagocytosis of cancer cells by macrophages, promotes antigen presentation, and activates antitumor T-cell immunity. Moreover, the bispecific targeting design of Fus-CVs ensures better targeting on tumor cells, but less on other cells, which reduces systemic side effects and enhances therapeutic efficacies. In malignant melanoma and mammary carcinoma models, we demonstrate that Fus-CVs significantly improve overall survival of model animals by inhibiting post-surgery tumor recurrence and metastasis. The Fus-CVs are suitable for protein display by genetic engineering. These advantages, integrated with other unique properties inherited from source cells, make Fus-CVs an attractive platform for multi-targeting immune checkpoint blockade therapy.
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Inhibidores de Puntos de Control Inmunológico/inmunología , Inmunoterapia , Neoplasias/terapia , Proteínas Recombinantes de Fusión/inmunología , Animales , Antígeno B7-H1/inmunología , Antígeno CD47/inmunología , Línea Celular Tumoral , Femenino , Ratones , Neoplasias/inmunología , Proteínas Recombinantes de Fusión/genéticaRESUMEN
The immune system plays a critical role in the establishment, development, and progression of head and neck squamous cell carcinoma (HNSCC). As treatment with single-immune checkpoint agent results in a lower response rate in patients, it is important to investigate new strategies to maintain favorable anti-tumor immune response. Herein, the combination immunotherapeutic value of CTLA4 blockade and SFKs inhibition was assessed in transgenic HNSCC mouse model. Our present work showed that tumor growth was not entirely controlled when HNSCC model mice were administered anti-CTLA4 chemotherapeutic treatment. Moreover, it was observed that Src family kinases (SFKs) were hyper-activated and lack of anti-tumor immune responses following anti-CTLA4 chemotherapeutic treatment. We hypothesized that activation of SFKs is a mechanism of anti-CTLA4 immunotherapy resistance. We, therefore, carried out combined drug therapy using anti-CTLA4 mAbs and an SFKs' inhibitor, dasatinib. As expected, dasatinib and anti-CTLA4 synergistically inhibited tumor growth in Tgfbr1/Pten 2cKO mice. Furthermore, dasatinib and anti-CTLA4 combined to reduce the number of myeloid-derived suppressor cells and Tregs, increasing the CD8+ T cell-to-Tregs ratio. We also found that combining dasatinib with anti-CTLA4 therapy significantly attenuated the expression of p-STAT3Y705 and Ki67 in tumoral environment. These results suggest that combination therapy with SFKs inhibitors may be a useful therapeutic approach to increase the efficacy of anti-CTLA4 immunotherapy in HNSCC.
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Anticuerpos Monoclonales/uso terapéutico , Antígeno CTLA-4/inmunología , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/patología , Inhibidores de Proteínas Quinasas/uso terapéutico , Familia-src Quinasas/metabolismo , Animales , Linfocitos T CD4-Positivos/citología , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD8-positivos/citología , Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/terapia , Dasatinib/uso terapéutico , Modelos Animales de Enfermedad , Regulación hacia Abajo/efectos de los fármacos , Quimioterapia Combinada , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/terapia , Inmunoterapia , Ratones , Ratones Noqueados , Fosfohidrolasa PTEN/deficiencia , Fosfohidrolasa PTEN/genética , Inhibidores de Proteínas Quinasas/farmacología , Proteínas Serina-Treonina Quinasas/deficiencia , Proteínas Serina-Treonina Quinasas/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/deficiencia , Receptores de Factores de Crecimiento Transformadores beta/genética , Factor de Transcripción STAT3/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello , Microambiente Tumoral , Familia-src Quinasas/antagonistas & inhibidoresRESUMEN
Epithelial-mesenchymal transition (EMT) is associated with metastasis formation, generation and maintenance of cancer stem cells (CSCs). However, the regulatory mechanisms of CSCs have not been clarified. This study aims to investigate the role of TNF receptor-associated factor 6 (TRAF6) on EMT and CSC regulation in squamous cell carcinoma of head and neck (SCCHN). We found TRAF6 was overexpressed in human SCCHN tissues, and high TRAF6 expression was associated with lymphatic metastasis and resulted in poor prognosis in patients with SCCHN. In addition, elevated TRAF6 expression was observed in several HNSCC cell lines, and wound healing and transwell assay results showed that TRAF6 knockdown inhibited the migration and invasion ability of the SCCHN cells. Moreover, the expression of Vimentin, Slug and N-cadherin was down-regulated and that of E-cadherin was elevated after TRAF6 knockdown but decreased by transforming growth factor beta 1 (TGF-ß1) and CAL27 similar to mesenchymal cells formed after TGF-ß1 induction. In addition, the expression levels of CD44, ALDH1, KLF4 and SOX2 were inhibited after TRAF6 knockdown, and the anchor-dependent colony formation number and sphere number were remarkably reduced. Flow cytometry showed TRAF6 knockdown reduced ALDH1-positive cancer stem cells. We also demonstrated that TRAF6 is closely associated with EMT process and cancer stem cells using a Tgfbr1/Pten 2cKO mice SCCHN model and human SCCHN tissue microarray. Our findings indicate that TRAF6 plays a role in EMT phenotypes, the generation and maintenance of CSCs in SCCHN, suggesting that TRAF6 is a potential therapeutic target for SCCHN.
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Transición Epitelial-Mesenquimal , Células Madre Neoplásicas/metabolismo , Células Madre Neoplásicas/patología , Carcinoma de Células Escamosas de Cabeza y Cuello/metabolismo , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Factor 6 Asociado a Receptor de TNF/metabolismo , Animales , Biomarcadores de Tumor/metabolismo , Línea Celular Tumoral , Humanos , Factor 4 Similar a Kruppel , Metástasis Linfática/patología , Ratones Noqueados , Invasividad Neoplásica , Metástasis de la Neoplasia , FenotipoRESUMEN
The adenosine-induced immunosuppression hampers the immune response toward tumor cells and facilitates the tumor cells to evade immunosurveillance. CD73, an ecto-5-nucleotidase, is the ectoenzyme dephosphorylating extracellular AMP to adenosine. Here, using immunocompetent transgenic head and neck squamous cell carcinoma (HNSCC) mouse model, immune profiling showed high expression of CD73 on CD4+ and CD8+ T cells was associated with an "exhausted" phenotype. Further, treatment with anti-CD73 monoclonal antibody (mAb) significantly blunted the tumor growth in the mouse model, and the blockade of CD73 reversed the "exhausted" phenotype of CD4+ and CD8+ T cells through downregulation of total expression of PD-1 and CTLA-4 on T cells. Whereas the population of CD4+ CD73hi /CD8+ CD73hi T cells expressed higher CTLA-4 and PD-1 as compared to untreated controls. In addition, the human tissue microarrays showed the expression of CD73 is upregulated on tumor infiltrating immune cells in patients with primary HNSCC. Moreover, CD73 expression is an independent prognostic factor for poor outcome in our cohort of HNSCC patients. Altogether, these findings highlight the immunoregulatory role of CD73 in the development of HNSCC and we propose that CD73 may prove to be a promising immunotherapeutic target for the treatment of HNSCC.
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5'-Nucleotidasa/metabolismo , Linfocitos T CD8-positivos/inmunología , Carcinoma de Células Escamosas/inmunología , Neoplasias de Cabeza y Cuello/inmunología , Tolerancia Inmunológica/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , 5'-Nucleotidasa/antagonistas & inhibidores , 5'-Nucleotidasa/genética , Animales , Anticuerpos Monoclonales/farmacología , Apoptosis , Biomarcadores de Tumor , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD4-Positivos/metabolismo , Linfocitos T CD4-Positivos/patología , Linfocitos T CD8-positivos/metabolismo , Linfocitos T CD8-positivos/patología , Antígeno CTLA-4/metabolismo , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proliferación Celular , Estudios de Seguimiento , Proteínas Ligadas a GPI/antagonistas & inhibidores , Proteínas Ligadas a GPI/genética , Proteínas Ligadas a GPI/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Linfocitos Infiltrantes de Tumor/metabolismo , Linfocitos Infiltrantes de Tumor/patología , Ratones , Ratones Noqueados , Ratones Transgénicos , Fosfohidrolasa PTEN/fisiología , Fenotipo , Pronóstico , Receptor Tipo I de Factor de Crecimiento Transformador beta/fisiología , Tasa de Supervivencia , Células Tumorales CultivadasRESUMEN
Immune evasion is a hallmark feature of cancer, and it plays an important role in tumour initiation and progression. In addition, tumour immune evasion severely hampers the desired antitumour effect in multiple cancers. In this study, we aimed to investigate the role of the Notch pathway in immune evasion in the head and neck squamous cell carcinoma (HNSCC) microenvironment. We first demonstrated that Notch1 signaling was activated in a Tgfbr1/Pten-knockout HNSCC mouse model. Notch signaling inhibition using a γ-secretase inhibitor (GSI-IX, DAPT) decreased tumour burden in the mouse model after prophylactic treatment. In addition, flow cytometry analysis indicated that Notch signaling inhibition reduced the sub-population of myeloid-derived suppressor cells (MDSCs), tumour-associated macrophages (TAMs) and regulatory T cells (Tregs), as well as immune checkpoint molecules (PD1, CTLA4, TIM3 and LAG3), in the circulation and in the tumour. Immunohistochemistry (IHC) of human HNSCC tissues demonstrated that elevation of the Notch1 downstream target HES1 was correlated with MDSC, TAM and Treg markers and with immune checkpoint molecules. These results suggest that modulating the Notch signaling pathway may decrease MDSCs, TAMs, Tregs and immune checkpoint molecules in HNSCC.
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Secretasas de la Proteína Precursora del Amiloide/antagonistas & inhibidores , Carcinoma de Células Escamosas/inmunología , Diaminas/farmacología , Modelos Animales de Enfermedad , Neoplasias de Cabeza y Cuello/inmunología , Células Mieloides/inmunología , Linfocitos T Reguladores/inmunología , Tiazoles/farmacología , Animales , Apoptosis , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/metabolismo , Carcinoma de Células Escamosas/patología , Proliferación Celular , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de Cabeza y Cuello/patología , Humanos , Terapia de Inmunosupresión , Ratones , Ratones Noqueados , Células Mieloides/efectos de los fármacos , Fosfohidrolasa PTEN/fisiología , Proteínas Serina-Treonina Quinasas/fisiología , Receptor Notch1/genética , Receptor Notch1/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/fisiología , Linfocitos T Reguladores/efectos de los fármacos , Células Tumorales Cultivadas , Escape del Tumor/efectos de los fármacosRESUMEN
Nanotechnology possesses the potential to revolutionize the diagnosis and treatment of tumors. The ideal nanoparticles used for in vivo cancer therapy should have long blood circulation times and active cancer targeting. Additionally, they should be harmless and invisible to the immune system. Here, we developed a biomimetic nanoplatform with the above properties for cancer therapy. Macrophage membranes were reconstructed into vesicles and then coated onto magnetic iron oxide nanoparticles (Fe3O4 NPs). Inherited from the Fe3O4 core and the macrophage membrane shell, the resulting Fe3O4@MM NPs exhibited good biocompatibility, immune evasion, cancer targeting and light-to-heat conversion capabilities. Due to the favorable in vitro and in vivo properties, biomimetic Fe3O4@MM NPs were further used for highly effective photothermal therapy of breast cancer in nude mice. Surface modification of synthetic nanomaterials with biomimetic cell membranes exemplifies a novel strategy for designing an ideal nanoplatform for translational medicine.
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Neoplasias de la Mama/terapia , Hipertermia Inducida/métodos , Terapia por Luz de Baja Intensidad/métodos , Nanopartículas de Magnetita/uso terapéutico , Terapia Molecular Dirigida/métodos , Nanomedicina Teranóstica/métodos , Animales , Transporte Biológico , Neoplasias de la Mama/metabolismo , Neoplasias de la Mama/patología , Membrana Celular/inmunología , Membrana Celular/metabolismo , Femenino , Óxido Ferrosoférrico/química , Óxido Ferrosoférrico/metabolismo , Humanos , Evasión Inmune , Células MCF-7 , Nanopartículas de Magnetita/ultraestructura , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos ICR , Ratones Desnudos , Células RAW 264.7 , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
AIM: p21-activated kinase 2 (PAK2) is overexpressed in several tumors but the expression of PAK2 in oral squamous cell carcinomas (OSCCs) remains unclear. MATERIALS & METHODS: Immunohistochemistry was performed on human tissue microarrays containing 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa. RESULTS: PAK2 expression was increased in primary OSCC compared with normal mucosa and significantly increased in primary OSCC grade III compared with grade I, but independent of overall survival rate. Moreover, the expression of PAK2 was statistically correlated with Lck/Yes novel tyrosine kinase (LYN), zinc finger transcription factor Slug, tumor-associated macrophage marker CD163 and LAG3. CONCLUSION: Overexpression of PAK2 in OSCC may be associated with an advanced pathology grade.
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Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas/genética , Neoplasias de la Boca/genética , Quinasas p21 Activadas/genética , Adulto , Anciano , Antígenos CD/genética , Antígenos de Diferenciación Mielomonocítica/genética , Carcinoma de Células Escamosas/patología , Supervivencia sin Enfermedad , Femenino , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Estimación de Kaplan-Meier , Masculino , Persona de Mediana Edad , Mucosa Bucal/metabolismo , Mucosa Bucal/patología , Neoplasias de la Boca/patología , Clasificación del Tumor , Proteínas de Neoplasias/genética , Pronóstico , Receptores de Superficie Celular/genética , Análisis de Matrices TisularesRESUMEN
Immature myeloid cells including myeloid-derived suppressor cells (MDSCs) and tumour-associated macrophages (TAMs) promote tumour growth and metastasis by facilitating tumour transformation and angiogenesis, as well as by suppressing antitumour effector immune responses. Therefore, strategies designed to reduce MDSCs and TAMs accumulation and their activities are potentially valuable therapeutic goals. In this study, we show that negative immune checkpoint molecule B7-H3 is significantly overexpressed in human head and neck squamous cell carcinoma (HNSCC) specimen as compared with normal oral mucosa. Using immunocompetent transgenic HNSCC models, we observed that targeting inhibition of B7-H3 reduced tumour size. Flow cytometry analysis revealed that targeting inhibition of B7-H3 increases antitumour immune response by decreasing immunosuppressive cells and promoting cytotoxic T cell activation in both tumour microenvironment and macroenvironment. Our study provides direct in vivo evidence for a rationale for B7-H3 blockade as a future therapeutic strategy to treat patients with HNSCC.
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Antígenos B7/antagonistas & inhibidores , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/patología , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/patología , Células Mieloides/patología , Animales , Antígenos B7/metabolismo , Carcinogénesis/metabolismo , Carcinogénesis/patología , Modelos Animales de Enfermedad , Humanos , Macrófagos/patología , Ratones Noqueados , Células Mieloides/metabolismo , Células Supresoras de Origen Mieloide/patología , Pronóstico , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismoRESUMEN
BACKGROUND: Cancer immunotherapy offers a promising approach in cancer treatment. The adenosine A2A receptor (A2AR) could protect cancerous tissues from immune clearance via inhibiting T cells response. To date, the role of A2AR in head and neck squamous cell carcinoma (HNSCC) has not been investigated. Here, we sought to explore the expression and immunotherapeutic value of A2AR blockade in HNSCC. METHODS: The expression of A2AR was evaluated by immunostaining in 43 normal mucosae, 48 dysplasia and 165 primary HNSCC tissues. The immunotherapeutic value of A2AR blockade was assessed in vivo in genetically defined immunocompetent HNSCC mouse model. RESULTS: Immunostaining of HNSCC tissue samples revealed that increased expression of A2AR on tumor infiltrating immune cells correlated with advanced pathological grade, larger tumor size and positive lymph node status. Elevated A2AR expression was also detected in recurrent HNSCC and HNSCC tissues with induction chemotherapy. The expression of A2AR was found to be significantly correlated with HIF-1α, CD73, CD8 and Foxp3. Furthermore, the increased population of CD4+Foxp3+ regulatory T cells (Tregs), which partially expressed A2AR, was observed in an immunocompetent mouse model that spontaneously develops HNSCC. Pharmacological blockade of A2AR by SCH58261 delayed the tumor growth in the HNSCC mouse model. Meanwhile, A2AR blockade significantly reduced the population of CD4+ Foxp3+ Tregs and enhanced the anti-tumor response of CD8+ T cells. CONCLUSIONS: These results offer a preclinical proof for the administration of A2AR inhibitor on prophylactic experimental therapy of HNSCC and suggest that A2AR blockade can be a potential novel strategy for HNSCC immunotherapy.
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Linfocitos T CD8-positivos/inmunología , Linfocitos T CD8-positivos/metabolismo , Carcinoma de Células Escamosas/inmunología , Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/inmunología , Neoplasias de Cabeza y Cuello/metabolismo , Inmunomodulación , Receptor de Adenosina A2A/metabolismo , Linfocitos T Reguladores/inmunología , Linfocitos T Reguladores/metabolismo , 5'-Nucleotidasa/metabolismo , Antagonistas del Receptor de Adenosina A2/farmacología , Adulto , Anciano , Animales , Biomarcadores , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patología , Citocinas/metabolismo , Modelos Animales de Enfermedad , Factores de Transcripción Forkhead/metabolismo , Expresión Génica , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/patología , Humanos , Subunidad alfa del Factor 1 Inducible por Hipoxia/metabolismo , Inmunohistoquímica , Quimioterapia de Inducción , Recuento de Linfocitos , Ratones , Ratones Transgénicos , Persona de Mediana Edad , Clasificación del Tumor , Metástasis de la Neoplasia , Fosfohidrolasa PTEN/genética , Proteínas Serina-Treonina Quinasas/metabolismo , Receptor de Adenosina A2A/genética , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/metabolismo , Recurrencia , Carcinoma de Células Escamosas de Cabeza y Cuello , Carga Tumoral/efectos de los fármacos , Ensayos Antitumor por Modelo de XenoinjertoRESUMEN
SRC family kinases (SFKs), a group of nonreceptor tyrosine kinases, modulate multiple cellular functions, such as cell proliferation, differentiation and metabolism. SFKs display aberrant activity in progressive stages of human cancers. However, the precise role of SFKs in the head and neck squamous cell carcinoma (HNSCC) signaling network is far from clear. In this study, we found that the inhibition of SFKs activity by dasatinib effectively reduced the tumor size and population of MDSCs in the HNSCC mouse model. Molecular analysis indicates that phosphorylation of LYN, rather than SRC, was inhibited by dasatinib treatment. Next, we analyzed LYN expression by immunostaining and found that it was overexpressed in the human HNSCC specimens. Moreover, LYN expression in stromal cells positively correlated with myeloid-derived suppressor cells (MDSCs) makers CD11b and CD33 in human HNSCC. The dual positive expression of LYN in epithelial and stromal cells (EPI+ SRT+ ) was associated with unfavorable overall survival of HNSCC patients. These findings indicate that SFKs may be a potential target for an effective immunotherapy of HNSCC by decreasing MDSCs and moreover, LYN will have an impact on such therapeutic strategy.
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Carcinoma de Células Escamosas/patología , Dasatinib/uso terapéutico , Neoplasias de Cabeza y Cuello/patología , Células Supresoras de Origen Mieloide/patología , Proteínas de Neoplasias/antagonistas & inhibidores , Inhibidores de Proteínas Quinasas/uso terapéutico , Familia-src Quinasas/antagonistas & inhibidores , Animales , Carcinoma de Células Escamosas/tratamiento farmacológico , Carcinoma de Células Escamosas/enzimología , Carcinoma de Células Escamosas/inmunología , Dasatinib/farmacología , Inducción Enzimática/efectos de los fármacos , Células Epiteliales/enzimología , Regulación Neoplásica de la Expresión Génica/efectos de los fármacos , Neoplasias de Cabeza y Cuello/tratamiento farmacológico , Neoplasias de Cabeza y Cuello/enzimología , Neoplasias de Cabeza y Cuello/inmunología , Humanos , Ratones , Ratones Noqueados , Terapia Molecular Dirigida , Proteínas de Neoplasias/fisiología , Fosfohidrolasa PTEN/deficiencia , Fosforilación/efectos de los fármacos , Inhibidores de Proteínas Quinasas/farmacología , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Serina-Treonina Quinasas/deficiencia , Receptor Tipo I de Factor de Crecimiento Transformador beta , Receptores de Factores de Crecimiento Transformadores beta/deficiencia , Células del Estroma/enzimología , Escape del Tumor , Regulación hacia Arriba , Ensayos Antitumor por Modelo de Xenoinjerto , Familia-src Quinasas/biosíntesis , Familia-src Quinasas/genética , Familia-src Quinasas/metabolismo , Familia-src Quinasas/fisiologíaRESUMEN
V-domain Ig suppressor of T cell activation (VISTA), a novel immune checkpoint regulatory molecule, suppresses T cell mediated immune responses. The aim of the present study was to profile the immunological expression, clinical significance and correlation of VISTA in human oral squamous cell carcinoma (OSCC). Human tissue microarrays, containing 165 primary OSCCs, 48 oral epithelial dysplasias and 43 normal oral mucosae, were applied to investigate the expression levels of VISTA, CD8, cytotoxic T lymphocyte-associated antigen 4 (CTLA-4), programmed death ligand 1 (PD-L1), PI3Kα p110, IL13Rα2, phospho-STAT3 at tyrosine 705 (p-STAT3) and myeloid-derived suppressor cell (MDSC) markers (CD11b and CD33) by immunohistochemistry and digital pathology analysis. The results demonstrated that the protein level of VISTA was significantly higher in human OSCC specimens, and that VISTA expression in primary OSCCs was correlated with lymph node status. VISTA expression did not serve as an independent predictor for poor prognosis, while patient subgroup with VISTA high and CD8 low expression (22/165) had significantly poorer overall survival compared with other subgroups based on the multivariate and Cox hazard analyses among the primary OSCC patients in the present cohort. Additionally, the expression of VISTA was significantly correlated with PD-L1, CTLA-4, IL13Rα2, PI3K, p-STAT3, CD11b and CD33 according to Pearson's correlation coefficient test. Taken together, the results indicated that the VISTA high and CD8 low group, as an immunosuppressive subgroup, might be associated with a poor prognosis in primary OSCC. These findings indicated that VISTA might be a potential immunotherapeutic target in OSCC treatment.
Asunto(s)
Antígenos B7/biosíntesis , Antígenos CD8/inmunología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/inmunología , Neoplasias de la Boca/inmunología , Antígeno B7-H1/biosíntesis , Antígeno CTLA-4/biosíntesis , Carcinoma de Células Escamosas/patología , Humanos , Terapia de Inmunosupresión , Neoplasias de la Boca/genética , Neoplasias de la Boca/patología , Pronóstico , Factor de Transcripción STAT3/biosíntesis , Análisis de SupervivenciaRESUMEN
Checkpoint blockade therapy utilizing monoclonal antibodies to reactivate T cells and recover their antitumor activity makes an epoch in cancer immunotherapy. The role of B7-H4, a novel negative immune checkpoint, in oral squamous cell carcinoma (OSCC) has still not been elucidated. In this study, tissue samples from human OSCC, which contains 165 primary OSCC, 48 oral epithelial dysplasia and 43 normal oral mucosa specimens, and Tgfbr1/Pten 2cKO mice OSCC model were stained with B7-H4 antibody to analyze the correlations between B7-H4 expression and clinicopathological characteristics. Kaplan-Meier analysis was used to compare the survival of patients with high B7-H4 expression and patients with low B7-H4 expression. We found B7-H4 is highly expressed in human OSCC tissue, and the B7-H4 expression level was associated with the clinicopathological parameters containing pathological grade and lymph node status. Moreover, we confirmed that B7-H4 was overexpressed in Tgfbr1/Pten 2cKO mice OSCC model. Our data also indicated that patients with high B7-H4 expression had poor overall survival compared with those with low B7-H4 expression. Furthermore, this study demonstrated that B7-H4 was positively associated with PD-L1, CD11b, CD33, PI3Kα p110, and p-S6 (S235/236). Taken together, these findings suggest B7-H4 is a potential target in the treatment of OSCC.
Asunto(s)
Carcinoma de Células Escamosas/metabolismo , Neoplasias de Cabeza y Cuello/metabolismo , Neoplasias de la Boca/metabolismo , Inhibidor 1 de la Activación de Células T con Dominio V-Set/biosíntesis , Animales , Carcinoma de Células Escamosas/patología , Línea Celular Tumoral , Modelos Animales de Enfermedad , Femenino , Neoplasias de Cabeza y Cuello/patología , Humanos , Ganglios Linfáticos/patología , Masculino , Ratones , Ratones Noqueados , Ratones Transgénicos , Neoplasias de la Boca/patología , Clasificación del Tumor , Carcinoma de Células Escamosas de Cabeza y Cuello , Análisis de Supervivencia , Análisis de Matrices TisularesRESUMEN
For decades, poly(ethylene glycol) (PEG) has been widely incorporated into nanoparticles for evading immune clearance and improving the systematic circulation time. However, recent studies have reported a phenomenon known as "accelerated blood clearance (ABC)" where a second dose of PEGylated nanomaterials is rapidly cleared when given several days after the first dose. Herein, we demonstrate that natural red blood cell (RBC) membrane is a superior alternative to PEG. Biomimetic RBC membrane-coated Fe(3)O(4) nanoparticles (Fe(3)O(4) @RBC NPs) rely on CD47, which is a "don't eat me" marker on the RBC surface, to escape immune clearance through interactions with the signal regulatory protein-alpha (SIRP-α) receptor. Fe(3)O(4) @RBC NPs exhibit extended circulation time and show little change between the first and second doses, with no ABC suffered. In addition, the administration of Fe(3)O(4) @RBC NPs does not elicit immune responses on neither the cellular level (myeloid-derived suppressor cells (MDSCs)) nor the humoral level (immunoglobulin M and G (IgM and IgG)). Finally, the in vivo toxicity of these cell membrane-camouflaged nanoparticles is systematically investigated by blood biochemistry, hematology testing, and histology analysis. These findings are significant advancements toward solving the long-existing clinical challenges of developing biomaterials that are able to resist both immune response and rapid clearance.
Asunto(s)
Materiales Biomiméticos/farmacología , Circulación Sanguínea/efectos de los fármacos , Materiales Biocompatibles Revestidos/farmacología , Membrana Eritrocítica/metabolismo , Nanopartículas/química , Animales , Compuestos Férricos/química , Hidrodinámica , Evasión Inmune , Macrófagos/efectos de los fármacos , Macrófagos/metabolismo , Ensayo de Materiales , Ratones , Nanopartículas/toxicidad , Nanopartículas/ultraestructura , Polietilenglicoles/química , Células RAW 264.7 , Electricidad Estática , Factores de Tiempo , Distribución Tisular/efectos de los fármacosRESUMEN
The suitable microenvironment of bone regeneration is critically important for periodontitis-derived bone defect repair. Three major challenges in achieving a robust osteogenic reaction are the exist of oral inflammation, pathogenic bacteria invasion and unaffluent seed cells. Herein, a customizable and multifunctional 3D-printing module was designed with glycidyl methacrylate (GMA) modified epsilon-poly-L-lysine (EPLGMA) loading periodontal ligament stem cells (PDLSCs) and myeloid-derived suppressive cells membrane vesicles (MDSCs-MV) bioink (EPLGMA/PDLSCs/MDSCs-MVs, abbreviated as EPM) for periodontitis-derived bone defect repair. The EPM showed excellent mechanical properties and physicochemical characteristics, providing a suitable microenvironment for bone regeneration.In vitro, EPMs presented effectively kill the periodontopathic bacteria depend on the natural antibacterial properties of the EPL. Meanwhile, MDSCs-MV was confirmed to inhibit T cells through CD73/CD39/adenosine signal pathway, exerting an anti-inflammatory role. Additionally, seed cells of PDLSCs provide an adequate supply for osteoblasts. Moreover, MDSCs-MV could significantly enhance the mineralizing capacity of PDLSCs-derived osteoblast. In the periodontal bone defect rat model, the results of micro-CT and histological staining demonstrated that the EPM scaffold similarly had an excellent anti-inflammatory and bone regeneration efficacyin vivo. This biomimetic and multifunctional 3D-printing bioink opens new avenues for periodontitis-derived bone defect repair and future clinical application.