RESUMO
Tumor immune escape is an important strategy of tumor survival. There are many mechanisms of tumor immune escape, including immunosuppression, which has become a research hotspot in recent years. The programmed death ligand-1/programmed death-1 (PD-L1/PD-1) signaling pathway is an important component of tumor immunosuppression, which can inhibit the activation of T lymphocytes and enhance the immune tolerance of tumor cells, thereby achieving tumor immune escape. Therefore, targeting the PD-L1/PD-1 pathway is an attractive strategy for cancer treatment; however, the therapeutic effectiveness of PD-L1/PD-1 remains poor. This situation requires gaining a deeper understanding of the complex and varied molecular mechanisms and factors driving the expression and activation of the PD-L1/PD-1 signaling pathway. In this review, we summarize the regulation mechanisms of the PD-L1/PD-1 signaling pathway in the tumor microenvironment and their roles in mediating tumor escape. Overall, the evidence accumulated to date suggests that induction of PD-L1 by inflammatory factors in the tumor microenvironment may be one of the most important factors affecting the therapeutic efficiency of PD-L1/PD-1 blocking.
Assuntos
Antígeno B7-H1/imunologia , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/imunologia , Evasão Tumoral/imunologia , Microambiente Tumoral/imunologia , Animais , Humanos , Transdução de Sinais/imunologia , Linfócitos T/imunologiaRESUMO
BACKGROUND: Natural killer (NK) cells have gained considerable attention and hold great potential for their application in tumor immunotherapy. This is mainly due to their MHC-unrestricted and pan-specific recognition capabilities, as well as their ability to rapidly respond to and eliminate target cells. To artificially generate therapeutic NK cells, various materials can be utilized, such as peripheral blood mononuclear cells (PBMCs), umbilical cord blood (UCB), induced pluripotent stem cells (iPSCs), and NK cell lines. Exploiting the therapeutic potential of NK cells to treat tumors through in vivo and in vitro therapeutic modalities has yielded positive therapeutic results. CONCLUSION: This review provides a comprehensive description of NK cell therapeutic approaches for tumors and discusses the current problems associated with these therapeutic approaches and the prospects of NK cell therapy for tumors.
Assuntos
Imunoterapia , Células Matadoras Naturais , Neoplasias , Humanos , Células Matadoras Naturais/imunologia , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia/métodos , AnimaisRESUMO
T cell engineering, particularly via chimeric antigen receptor (CAR) modifications for enhancing tumor specificity, has shown efficacy in treating hematologic malignancies. The extension of CAR-T cell therapy to solid tumors, however, is impeded by several challenges: The absence of tumor-specific antigens, antigen heterogeneity, a complex immunosuppressive tumor microenvironment, and physical barriers to cell infiltration. Additionally, limitations in CAR-T cell manufacturing capacity and the high costs associated with these therapies restrict their widespread application. The integration of nanomaterials into CAR-T cell production and application offers a promising avenue to mitigate these challenges. Utilizing nanomaterials in the production of CAR-T cells can decrease product variability and lower production expenses, positively impacting the targeting and persistence of CAR-T cells in treatment and minimizing adverse effects. This review comprehensively evaluates the use of various nanomaterials in the production of CAR-T cells, genetic modification, and in vivo delivery. It discusses their underlying mechanisms and potential for clinical application, with a focus on improving specificity and safety in CAR-T cell therapy.
Assuntos
Imunoterapia Adotiva , Nanoestruturas , Neoplasias , Receptores de Antígenos Quiméricos , Humanos , Nanoestruturas/química , Nanoestruturas/uso terapêutico , Neoplasias/terapia , Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Receptores de Antígenos Quiméricos/imunologia , Animais , Linfócitos T/imunologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
In South and Southeast Asia, the habit of chewing betel nuts is prevalent, which leads to oral submucous fibrosis (OSF). OSF is a well-established precancerous lesion, and a portion of OSF cases eventually progress to oral squamous cell carcinoma (OSCC). However, the specific molecular mechanisms underlying the malignant transformation of OSCC from OSF are poorly understood. In this study, the leading-edge techniques of Spatial Transcriptomics (ST) and Spatial Metabolomics (SM) are integrated to obtain spatial location information of cancer cells, fibroblasts, and immune cells, as well as the transcriptomic and metabolomic landscapes in OSF-derived OSCC tissues. This work reveals for the first time that some OSF-derived OSCC cells undergo partial epithelial-mesenchymal transition (pEMT) within the in situ carcinoma (ISC) region, eventually acquiring fibroblast-like phenotypes and participating in collagen deposition. Complex interactions among epithelial cells, fibroblasts, and immune cells in the tumor microenvironment are demonstrated. Most importantly, significant metabolic reprogramming in OSF-derived OSCC, including abnormal polyamine metabolism, potentially playing a pivotal role in promoting tumorigenesis and immune evasion is discovered. The ST and SM data in this study shed new light on deciphering the mechanisms of OSF-derived OSCC. The work also offers invaluable clues for the prevention and treatment of OSCC.
Assuntos
Carcinoma de Células Escamosas , Neoplasias de Cabeça e Pescoço , Neoplasias Bucais , Fibrose Oral Submucosa , Humanos , Fibrose Oral Submucosa/genética , Fibrose Oral Submucosa/metabolismo , Fibrose Oral Submucosa/patologia , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço , Transcriptoma , Microambiente Tumoral , Transformação Celular Neoplásica , Perfilação da Expressão GênicaRESUMO
BACKGROUND: N6-methyladenosine (m6A) modification is essential for modulating RNA processing as well as expression, particularly in the context of malignant tumour progression. However, the exploration of m6A modification in nasopharyngeal carcinoma (NPC) remains very limited. METHODS: RNA m6A levels were analysed in NPC using m6A dot blot assay. The expression level of methyltransferase-like 14 (METTL14) within NPC tissues was analysed from public databases as well as RT-qPCR and immunohistochemistry. The influences on METTL14 expression on NPC proliferation and metastasis were explored via in vitro as well as in vivo functional assays. Targeted genes of METTL14 were screened using the m6A and gene expression profiling microarray data. Actinomycin D treatment and polysome analysis were used to detect the half-life and translational efficiency of ANKRD22. Flow cytometry, immunofluorescence and immunoprecipitation were used to validate the role of ANKRD22 on lipid metabolism in NPC cells. ChIP-qPCR analysis of H3K27AC signalling near the promoters of METTL14, GINS3, POLE2, PLEK2 and FERMT1 genes. RESULTS: We revealed METTL14, in NPC, correlating with poor patient prognosis. In vitro and in vivo assays indicated METTL14 actively promoted NPC cells proliferation and metastasis. METTL14 catalysed m6A modification on ANKRD22 messenger ribonucleic acid (mRNA), recognized by the reader IGF2BP2, leading to increased mRNA stability and higher translational efficiency. Moreover, ANKRD22, a metabolism-related protein on mitochondria, interacted with SLC25A1 to enhance citrate transport, elevating intracellular acetyl-CoA content. This dual impact of ANKRD22 promoted lipid metabolism reprogramming and cellular lipid synthesis while upregulating the expression of genes associated with the cell cycle (GINS3 and POLE2) and the cytoskeleton (PLEK2 and FERMT1) through heightened epigenetic histone acetylation levels in the nucleus. Intriguingly, our findings highlighted elevated ANKRD22-mediated histone H3 lysine 27 acetylation (H3K27AC) signals near the METTL14 promoter, which contributes to a positive feedback loop perpetuating malignant progression in NPC. CONCLUSIONS: The identified METTL14-ANKRD22-SLC25A1 axis emerges as a promising therapeutic target for NPC, and also these molecules may serve as novel diagnostic biomarkers.
Assuntos
Metabolismo dos Lipídeos , Metiltransferases , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Metiltransferases/metabolismo , Metiltransferases/genética , Metabolismo dos Lipídeos/genética , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/metabolismo , Neoplasias Nasofaríngeas/patologia , RNA Mensageiro/metabolismo , RNA Mensageiro/genética , Progressão da Doença , Adenosina/análogos & derivados , Adenosina/metabolismo , Adenosina/genética , Camundongos , Animais , Regulação Neoplásica da Expressão Gênica/genética , Reprogramação MetabólicaRESUMO
BACKGROUND: APLNR is a G protein-coupled receptor and our previous study had revealed that APLNR could inhibit nasopharyngeal carcinoma (NPC) growth and metastasis. However, the role of APLNR in regulating PD-L1 expression and immune escape in NPC is unknown. METHODS: We analyzed the expression and correlation of APLNR and PD-L1 in NPC tissues and cells. We investigated the effect of APLNR on PD-L1 expression and the underlying mechanism in vitro and in vivo. We also evaluated the therapeutic potential of targeting APLNR in combination with PD-L1 antibody in a nude mouse xenograft model. RESULTS: We found that APLNR was negatively correlated with PD-L1 in NPC tissues and cells. APLNR could inhibit PD-L1 expression by binding to the FERM domain of JAK1 and blocking the interaction between JAK1 and IFNGR1, thus suppressing IFN-γ-mediated activation of the JAK1/STAT1 pathway. APLNR could also inhibit NPC immune escape by enhancing IFN-γ secretion and CD8+ T-cell infiltration and reducing CD8+ T-cell apoptosis and dysfunction. Moreover, the best effect was achieved in inhibiting NPC growth in nude mice when APLNR combined with PD-L1 antibody. CONCLUSIONS: Our study revealed a novel mechanism of APLNR regulating PD-L1 expression and immune escape in NPC and suggested that APLNR maybe a potential therapeutic target for NPC immunotherapy.
Assuntos
Antígeno B7-H1 , Camundongos Nus , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Evasão Tumoral , Animais , Feminino , Humanos , Masculino , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , Regulação para Baixo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Interferon gama/metabolismo , Janus Quinase 1/metabolismo , Camundongos Endogâmicos BALB C , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/patologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores Acoplados a Proteínas G/genética , Receptores Acoplados a Proteínas G/imunologia , Receptores de Interferon/genética , Receptores de Interferon/metabolismo , Fator de Transcrição STAT1/metabolismo , Evasão Tumoral/efeitos dos fármacos , Ensaios Antitumorais Modelo de XenoenxertoRESUMO
Circular Ribonucleic Acid (CircRNA) plays regulatory roles in many biological processes, such as tumors and metabolic diseases. Due to the fact that circRNA is more stable and conservative than linear RNA, circRNA has become a potential biomarker in early clinical diagnosis and biomedical research. Therefore, the quantification of circRNA expression level is of importance for understanding their functions and their applications for disease diagnosis and treatment. Nevertheless, due to the low abundance of circRNA, it is still a challenge for the analysis of circRNA in cells. Herein, we proposed a sensitive detection method for circRNA based on the T7 exonuclease-assisted cycling enzymatic amplification. The fluorescent sensor was constructed by a hairpin molecular beacon and T7 exonuclease. With the cycling enzymatic amplification process, this sensor achieved the limit of detection of 1 pM with a good linear correlation in the range of 0-100 pM (R2 = 0.9891) using circBART2.2 as a model. Furthermore, we applied the proposed method in the determination of circBART2.2 in cell lysates. The results demonstrated that this method has promising applications in early diagnosis of Epstein-Barr virus (EBV) infection-related diseases using circRNA as the biomarker.
Assuntos
Infecções por Vírus Epstein-Barr , RNA Circular , Contagem de Células , Herpesvirus Humano 4 , Humanos , Limite de Detecção , Espectrometria de FluorescênciaRESUMO
Epstein-Barr virus (EBV) is reportedly the first identified human tumor virus, and is closely related to the occurrence and development of nasopharyngeal carcinoma (NPC), gastric carcinoma (GC), and several lymphomas. PD-L1 expression is elevated in EBV-positive NPC and GC tissues; however, the specific mechanisms underlying the EBV-dependent promotion of PD-L1 expression to induce immune escape warrant clarification. EBV encodes 44 mature miRNAs. In this study, we find that EBV-miR-BART11 and EBV-miR-BART17-3p upregulate the expression of PD-L1 in EBV-associated NPC and GC. Furthermore, EBV-miR-BART11 targets FOXP1, EBV-miR-BART17-3p targets PBRM1, and FOXP1 and PBRM1 bind to the enhancer region of PD-L1 to inhibit its expression. Therefore, EBV-miR-BART11 and EBV-miR-BART17-3p inhibit FOXP1 and PBRM1, respectively, and enhance the transcription of PD-L1 (CD274, http://www.ncbi.nlm.nih.gov/gene/29126 ), resulting in the promotion of tumor immune escape, which provides insights into potential targets for EBV-related tumor immunotherapy.
Assuntos
Herpesvirus Humano 4/genética , MicroRNAs/genética , Carcinoma Nasofaríngeo/imunologia , Neoplasias Nasofaríngeas/imunologia , Neoplasias Gástricas/imunologia , Evasão Tumoral/imunologia , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Proteínas de Ligação a DNA/antagonistas & inibidores , Proteínas de Ligação a DNA/metabolismo , Infecções por Vírus Epstein-Barr/virologia , Fatores de Transcrição Forkhead/antagonistas & inibidores , Fatores de Transcrição Forkhead/metabolismo , Regulação Neoplásica da Expressão Gênica/genética , Herpesvirus Humano 4/imunologia , Humanos , Linfoma/imunologia , Linfoma/virologia , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/virologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/virologia , Proteínas Repressoras/antagonistas & inibidores , Proteínas Repressoras/metabolismo , Neoplasias Gástricas/virologia , Fatores de Transcrição/antagonistas & inibidores , Fatores de Transcrição/metabolismo , Evasão Tumoral/genética , Microambiente Tumoral/imunologiaRESUMO
Gossypol has been reported to exhibit antitumor effects against several human cancers. However, the anticancer effects of gossypol on nasopharyngeal carcinoma (NPC) have not been investigated. Against this backdrop, the present study was designed to evaluate the anticancer effects of gossypol against NPC cells and to identify the signaling pathways involved through bioinformatic analysis. Gossypol-inhibited death of NPC cells is concentration-dependent. To explore the underlying mechanism for gossypol's antitumor effect, microarray of gossypol-treated and -untreated NPC cells was performed. A total of 836 differentially expressing genes (DEGs) were identified in gossypol-treated NPC cells, of which 461 genes were upregulated and 375 genes were downregulated. The cellular components, molecular functions, biological processes, and signal pathways, in which the DEGs were involved, were identified by gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG). The Gene Set Enrichment Analysis (GSEA) predicted upstream transcription factors (TF) ETS2 and E2F1 that regulate DEGs. Weighted Gene Co-expression Network Analysis (WGCNA) was performed to identify a class of modules and genes related to DNA repair and cell cycle. TNFRSF10B, a receptor for death in NPC cells, was knocked down. The results suggested that the ability of NPC cells to resist gossypol killing was enhanced. In addition, to further investigate the possible molecular mechanisms, we constructed a transcriptional regulatory network of TNFRSF10B containing 109 miRNAs and 47 TFs. Taken together, our results demonstrated that gossypol triggered antitumor effects against NPC cells, indicating its applicability for the management of NPC.
Assuntos
Antineoplásicos/farmacologia , Redes Reguladoras de Genes , Gossipol/farmacologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/metabolismo , Transcriptoma , Proteínas de Ciclo Celular/genética , Proteínas de Ciclo Celular/metabolismo , Morte Celular/efeitos dos fármacos , Linhagem Celular Tumoral , Resistencia a Medicamentos Antineoplásicos/genética , Humanos , Transdução de Sinais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismoRESUMO
Epstein-Barr virus (EBV) infection is an established cause of nasopharyngeal carcinoma (NPC) and is involved in a variety of malignant phenotypes, including tumor immune escape. EBV can encode a variety of circular RNAs (circRNA), however, little is known regarding the biological functions of these circRNAs in NPC. In this study, EBV-encoded circBART2.2 was found to be highly expressed in NPC where it upregulated PD-L1 expression and inhibited T-cell function in vitro and in vivo. circBART2.2 promoted transcription of PD-L1 by binding the helicase domain of RIG-I and activating transcription factors IRF3 and NF-κB, resulting in tumor immune escape. These results elucidate the biological function of circBART2.2, explain a novel mechanism of immune escape caused by EBV infection, and provide a new immunotherapy target for treating NPC. SIGNIFICANCE: This work demonstrates that circBART2.2 binding to RIG-I is essential for the regulation of PD-L1 and subsequent immune escape in nasopharyngeal carcinoma.
Assuntos
Antígeno B7-H1/genética , Herpesvirus Humano 4/genética , Carcinoma Nasofaríngeo/etiologia , RNA Circular/genética , RNA Viral/genética , Evasão Tumoral/genética , Animais , Antígeno B7-H1/metabolismo , Linhagem Celular Tumoral , Citotoxicidade Imunológica/genética , Proteína DEAD-box 58/genética , Proteína DEAD-box 58/metabolismo , Modelos Animais de Doenças , Suscetibilidade a Doenças , Infecções por Vírus Epstein-Barr/complicações , Infecções por Vírus Epstein-Barr/virologia , Regulação Neoplásica da Expressão Gênica , Humanos , Camundongos , NF-kappa B/metabolismo , Carcinoma Nasofaríngeo/metabolismo , Carcinoma Nasofaríngeo/patologia , Ligação Proteica , Interferência de RNA , Receptores Imunológicos/genética , Receptores Imunológicos/metabolismoRESUMO
Metastasis is a critical cause of treatment failure and death in patients with advanced malignancies. Tumor cells can leave the primary site and enter the bloodstream; these circulating tumor cells then colonize target organs by overcoming blood shear stress, evading immune surveillance, and silencing the offensive capabilities of immune cells, eventually forming metastatic foci. From leaving the primary focus to the completion of distant metastasis, malignant tumor cells are supported and/or antagonized by certain immune cells. In particular, it has been found that myeloid granulocytes play an important role in this process. This review therefore aims to comprehensively describe the significance of neutrophils in solid tumor metastasis in terms of their supporting role in initiating the invasion and migration of tumor cells and assisting the colonization of circulating tumor cells in distant target organs, with the hope of providing insight into and ideas for anti-tumor metastasis treatment of tumor patients.
Assuntos
Metástase Neoplásica , Neutrófilos/fisiologia , Plaquetas/fisiologia , Movimento Celular , Humanos , Invasividade Neoplásica , Metástase Neoplásica/prevenção & controle , Células Neoplásicas Circulantes/patologiaRESUMO
Objective: To investigate the correlation between the BRAF V600E gene mutation and clinicopathological features and thyroid function after iodine-131 treatment in patients with papillary thyroid cancer (PTC). Methods: A total of 128 PTC patients who underwent iodine-131 treatment after a total thyroidectomy from February 2015 to November 2016 at Hunan Cancer Hospital, China, were recruited. There were 25 males and 103 females. The age range was 11 to 73 years old. The BRAF V600E mutation in tumor tissues was detected by amplification-restriction mutation system polymerase chain reaction (ARMS-PCR), and the serum levels of Tg, TSH, Tg-Ab, and Tpo-Ab were measured by chemiluminescence after iodine-131 treatment. The BRAF V600E mutation was shown to be associated with clinicopathological characteristics and thyroid function indicators after iodine-131 treatment. Results: BRAF V600E mutation was detected in 75 of the 128 patients (58.6%) and was observed more frequently in cases with elevated Tg levels (Tg>1.00) at 3, 6, 12, and 18 months after treatment compared with patients without any BRAF mutations (P<0.05). Patients with BRAF V600E mutation had significant lower level of Tg-Ab at 3 and 12 months after treatment with iodine-131 than patients without BRAF V600E mutation (P<0.05). Among the 75 BRAF V600E patients, no significant association was found between the levels of TSH and Tpo-Ab after iodine-131 treatment (P>0.05). The BRAF V600E mutation was closely associated with the high-risk and age of the patient (≥45 years old) (P<0.05), but there was no significant correlation with gender, clinical stage, and distant metastasis. Conclusion: The BRAF V600E mutation is closely related to serum Tg elevation after treatment with iodine-131 in papillary thyroid cancer. These findings suggest that this BRAF mutation may be a predictor of the efficacy of iodine-131 treatment for papillary thyroid cancer.
RESUMO
Nasopharyngeal carcinoma (NPC) is one of the most malignant tumors in Southern China and southeast Asia, which is characterized by a dense lymphocyte infiltration and a poor prognosis. The emergence of single-cell sequencing represents a powerful tool to resolve tumor heterogeneity and delineate the complex communication among the tumor cells with neighboring stromal and immune cells in the tumor microenvironment (TME). Here, we performed single cell RNA-seq and analyzed tumor cells together with the infiltrating immune cells from three NPC tumor tissues. In our study, the malignant cells display the intra- and inter-tumoral heterogeneity among the individual patients. Analysis of the immune cells reveal the heterogeneous composition of the distinct immune cells and the various functional states of T cells in NPC tumors. Additionally, coupled with the reconstruct of the T cell receptor (TCR) sequences from immune cells full-length single-cell sequence data, we identify the diverse T cell clonotypes and expansion distribution in individual tumors. Overall, we firstly reveal the landscape of tumor and infiltrating immune cells in nasopharyngeal cancer. These results provide deeper insights on the mechanisms of tumor clearance by immune cells in the surrounding microenvironment, which will be helpful in improving the targeted and immune therapies for NPC.