RESUMO
Introduction: Gliomas are the most common and aggressive type of primary brain tumor, with a poor prognosis despite current treatment approaches. Understanding the molecular mechanisms underlying glioma development and progression is critical for improving therapies and patient outcomes. Methods: The current study comprehensively analyzed large-scale single-cell RNA sequencing and bulk RNA sequencing of glioma samples. By utilizing a series of advanced computational methods, this integrative approach identified the gene UPP1 (Uridine Phosphorylase 1) as a novel driver of glioma tumorigenesis and immune evasion. Results: High levels of UPP1 were linked to poor survival rates in patients. Functional experiments demonstrated that UPP1 promotes tumor cell proliferation and invasion and suppresses anti-tumor immune responses. Moreover, UPP1 was found to be an effective predictor of mutation patterns, drug response, immunotherapy effectiveness, and immune characteristics. Conclusions: These findings highlight the power of combining diverse machine learning methods to identify valuable clinical markers involved in glioma pathogenesis. Identifying UPP1 as a tumor growth and immune escape driver may be a promising therapeutic target for this devastating disease.
Assuntos
Neoplasias Encefálicas , Glioma , Aprendizado de Máquina , Evasão Tumoral , Humanos , Glioma/genética , Glioma/imunologia , Glioma/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/imunologia , Neoplasias Encefálicas/patologia , Evasão Tumoral/genética , Regulação Neoplásica da Expressão Gênica , Oncogenes , Biomarcadores Tumorais/genética , Linhagem Celular Tumoral , Carcinogênese/genética , Carcinogênese/imunologia , Animais , Prognóstico , CamundongosRESUMO
Immune evasion represents a crucial milestone in the progression of cancer and serves as the theoretical foundation for tumor immunotherapy. In this study, we reveal a negative association between Human Papillomavirus (HPV)-encoded circular RNA, circE7, and the infiltration of CD8+ T cells in head and neck squamous cell carcinoma (HNSCC). Both in vitro and in vivo experiments demonstrate that circE7 suppresses the function and activity of T cells by downregulating the transcription of LGALS9, which encodes the galectin-9 protein. The molecular mechanism involves circE7 binding to acetyl-CoA carboxylase 1 (ACC1), promoting its dephosphorylation and thereby activating ACC1. Activated ACC1 reduces H3K27 acetylation at the LGALS9 gene promoter, leading to decreased galectin-9 expression. Notably, galectin-9 interacts with immune checkpoint molecules TIM-3 and PD-1, inhibiting the secretion of cytotoxic cytokines by T cells and promoting T cell apoptosis. Here, we demonstrate a mechanism by which HPV promotes immune evasion in HNSCC through a circE7-driven epigenetic modification and propose a potential immunotherapy strategy for HNSCC that involves the combined use of anti-PD-1 and anti-TIM-3 inhibitors.
Assuntos
Linfócitos T CD8-Positivos , Galectinas , Neoplasias de Cabeça e Pescoço , Evasão da Resposta Imune , RNA Circular , Carcinoma de Células Escamosas de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/imunologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/virologia , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/imunologia , Neoplasias de Cabeça e Pescoço/virologia , Neoplasias de Cabeça e Pescoço/genética , Animais , Galectinas/genética , Galectinas/metabolismo , Galectinas/imunologia , Linfócitos T CD8-Positivos/imunologia , Linhagem Celular Tumoral , RNA Circular/genética , RNA Circular/metabolismo , RNA Circular/imunologia , Evasão da Resposta Imune/genética , Camundongos , Papillomaviridae/genética , Infecções por Papillomavirus/imunologia , Infecções por Papillomavirus/virologia , Infecções por Papillomavirus/genética , Regulação Neoplásica da Expressão Gênica , Evasão Tumoral/genética , Receptor Celular 2 do Vírus da Hepatite A/genética , Receptor Celular 2 do Vírus da Hepatite A/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/imunologia , Masculino , Apoptose/genética , Feminino , Epigênese Genética , RNA Viral/genética , RNA Viral/imunologia , Papillomavirus HumanoRESUMO
Objective To investigate the impact of dipeptidyl peptidase 3 (DPP3) on the immune escape of gastric cancer cells by regulating the expression of major histocompatibility complex class I chain-related gene B (MICB). Methods Knocking down DPP3 in MKN-45 human gastric cancer cells and overexpressing DPP3 in MGC-803 human gastric cancer cells, observing changes in cell proliferation, migration ability, and responses to natural killer (NK) cell cytotoxicity; using whole-transcriptome sequencing to identify the MICB gene, and knocking down MICB in DPP3-overexpressing cells to verify changes in cellular behavior. In C57 mice, the in vivo tumorigenic ability of DPP3-knockout cells and the infiltration of CD56+ cells in tissues were examined. Results Knocking out DPP3 promoted the proliferation and migration of gastric cancer cells, reduced MICB expression, and made the cells less sensitive to NK cell cytotoxicity; the tumorigenic ability in mice increased and CD56+ cells tissue infiltration decreased by DPP3 knocking out in the gastric cancer cells, but DPP3 overexpression showed the opposite results. Knocking down MICB could reverse the phenotypic changes induced by high DPP3 expression. Conclusion DPP3 inhibits the immune escape of gastric cancer cells by downregulating MICB expression.
Assuntos
Dipeptidil Peptidases e Tripeptidil Peptidases , Regulação para Baixo , Antígenos de Histocompatibilidade Classe I , Células Matadoras Naturais , Neoplasias Gástricas , Evasão Tumoral , Animais , Humanos , Camundongos , Linhagem Celular Tumoral , Movimento Celular/genética , Proliferação de Células/genética , Dipeptidil Peptidases e Tripeptidil Peptidases/genética , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Antígenos de Histocompatibilidade Classe I/imunologia , Células Matadoras Naturais/imunologia , Camundongos Endogâmicos C57BL , Neoplasias Gástricas/genética , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/patologia , Evasão Tumoral/genéticaRESUMO
Cancer remains a global health burden, shaped by both genetic mutations and epigenetic dysregulation. Epigenetic alteration plays a pivotal role in tumorigenesis, immune response modulation, and the emergence of treatment resistance. This review emphasizes the intricate interplay between epigenetically reprogrammed cancer cells and the tumor microenvironment (TME), a relationship central to the immunoediting concept, which encompasses elimination, equilibrium, and escape phases. This review highlights the significance of CD8+ T cells as potent anticancer agents and discusses the mechanisms by which tumor cells evade immune surveillance and evolve resistance to immunotherapy. Such evasion entails the regulation of inhibitory molecules, antigen presentation machinery, and cytokine milieu. Furthermore, this review explores the complex dynamics culminating in CD8+ T cell dysfunction within the TME. In summary, this work offers insights into the indispensable role of epigenetic mechanisms in bolstering cancer cell survival amidst immunological challenges within the TME.
Assuntos
Linfócitos T CD8-Positivos , Epigênese Genética , Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , Neoplasias/imunologia , Neoplasias/genética , Linfócitos T CD8-Positivos/imunologia , Imunoterapia/métodos , Evasão Tumoral/genética , AnimaisRESUMO
Aberrant activation of IL-18 signaling regulates tumor immune evasion and progression. However, the underlying mechanism remains unclear. Here, we report that long-chain acyl-CoA synthase 6 (ACSL6) is highly expressed in liver cancer and correlated with poor prognosis. ACSL6 promotes tumor growth, metastasis, and immune evasion mediated by IL-18, independent of its metabolic enzyme activity. Mechanistically, upon IL-18 stimulation, ACSL6 is phosphorylated by ERK2 at S674 and recruits IL-18RAP to interact with IL-18R1, thereby reinforcing the IL-18R1-IL-18RAP heterodimer and triggering NF-κB-dependent gene expression to facilitate tumor development. Furthermore, the up-regulation of CXCL1 and CXCL5 by ACSL6 promotes tumor-associated neutrophil and tumor-associated macrophage recruitment, thereby inhibiting cytotoxic CD8+ T cell infiltration. Ablation or S674A mutation of ACSL6 potentiated anti-PD-1 therapeutic efficacy by increasing the effector activity of intertumoral CD8+ T cells. We revealed that ACSL6 is a potential adaptor that activates IL-18-NF-κB axis-mediated tumor immune evasion and provides valuable insights for developing effective immunotherapy strategies for cancer.
Assuntos
Coenzima A Ligases , Interleucina-18 , NF-kappa B , Animais , Feminino , Humanos , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Coenzima A Ligases/metabolismo , Coenzima A Ligases/genética , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Interleucina-18/metabolismo , Interleucina-18/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/genética , Neoplasias/metabolismo , Neoplasias/patologia , Neoplasias/genética , Neoplasias/imunologia , NF-kappa B/metabolismo , Fosforilação , Receptores de Interleucina-18/metabolismo , Receptores de Interleucina-18/genética , Transdução de Sinais , Evasão Tumoral/genéticaRESUMO
Immune evasion is not only critical for tumor initiation and progression, but also determines the efficacy of immunotherapies. Through iterative in vivo CRISPR screens with seven syngeneic tumor models, we identified core and context-dependent immune evasion pathways across cancer types. This valuable high-confidence dataset is available for the further understanding of tumor intrinsic immunomodulators, which may lead to the discovery of effective anticancer therapeutic targets. With a focus on triple-negative breast cancer (TNBC), we found that Mga knock-out significantly enhances antitumor immunity and inhibits tumor growth. Transcriptomics and single-cell RNA sequencing analyses revealed that Mga influences various immune-related pathways in the tumor microenvironment. Our findings suggest that Mga may play a role in modulating the tumor immune landscape, though the precise mechanisms require further investigation. Interestingly, we observed that low MGA expression in breast cancer patients correlates with a favorable prognosis, particularly in those with active interferon-γ signaling. These observations provide insights into tumor immune escape mechanisms and suggest that further exploration of MGA's function could potentially lead to effective therapeutic strategies in TNBC.
Assuntos
Imunoterapia , Neoplasias de Mama Triplo Negativas , Microambiente Tumoral , Animais , Feminino , Humanos , Camundongos , Linhagem Celular Tumoral , Repetições Palindrômicas Curtas Agrupadas e Regularmente Espaçadas/genética , Sistemas CRISPR-Cas , Regulação Neoplásica da Expressão Gênica , Imunoterapia/métodos , Interferon gama/metabolismo , Interferon gama/imunologia , Interferon gama/genética , Neoplasias de Mama Triplo Negativas/genética , Neoplasias de Mama Triplo Negativas/imunologia , Neoplasias de Mama Triplo Negativas/terapia , Evasão Tumoral/genética , Microambiente Tumoral/imunologia , Microambiente Tumoral/genéticaRESUMO
Clear cell renal cell carcinoma (ccRCC) represents a prevalent malignancy of the urinary system. Despite the integration of immune checkpoint inhibitors (ICIs) into the treatment paradigm for advanced RCC, resistance to immunotherapy has emerged as a pivotal determinant impacting the clinical outlook of ccRCC. Accumulating evidence underscores the pivotal role of immune evasion-related genes and pathways in enabling tumor escape from host immune surveillance, consequently influencing patients' responsiveness to immunotherapy. Nonetheless, the clinical relevance of immune evasion-related genes in ccRCC patients undergoing immunotherapy remains inadequately understood. In this study, we aggregated RNA sequencing and clinical data from ccRCC patients across three cohorts: the Cancer Genome Atlas (TCGA), CheckMate cohorts, and the JAVELIN Renal 101 trial. Leveraging a curated immune evasion-related gene set from Lawson et al., we employed the LASSO algorithm and Cox regression analysis to identify eight genes (LPAR6, RGS5, NFYC, PCDH17, CENPW, CNOT8, FOXO3, SNRPB) significantly associated with immune therapy prognosis (HR, 3.57; 95 % CI, 2.38-5.35; P<0.001). A predictive algorithm developed utilizing these genes exhibited notable accuracy in forecasting patients' progression-free survival in the training set (AUC, 0.835). Furthermore, stratification of patients by risk score revealed discernible differences in immunotherapy response and tumor microenvironment. In summary, we present a prognostic model intricately linked with immune status and treatment response. For ccRCC patients undergoing immunotherapy, this approach holds promise in aiding clinical decision-making by providing more precise and tailored treatment recommendations.
Assuntos
Carcinoma de Células Renais , Imunoterapia , Neoplasias Renais , Carcinoma de Células Renais/genética , Carcinoma de Células Renais/imunologia , Carcinoma de Células Renais/terapia , Humanos , Neoplasias Renais/genética , Neoplasias Renais/imunologia , Neoplasias Renais/terapia , Neoplasias Renais/mortalidade , Imunoterapia/métodos , Prognóstico , Masculino , Feminino , Evasão da Resposta Imune/genética , Biomarcadores Tumorais/genética , Inibidores de Checkpoint Imunológico/uso terapêutico , Pessoa de Meia-Idade , Regulação Neoplásica da Expressão Gênica , Idoso , Evasão Tumoral/genéticaRESUMO
Immune escape and metabolic reprogramming are two essential hallmarks of cancer. Mucin-16 (MUC16) has been linked to glycolysis and immune response in different cancers. However, its involvement in nasopharyngeal carcinoma (NPC) has not been well described. We seek to dissect the functions and detailed mechanisms of MUC16 in NPC. Bioinformatics prediction was performed to identify NPC-related molecules. MUC16 was significantly enhanced in NPC tissues, which was correlated with the advanced tumor stage of patients. Lentiviral plasmids-mediated MUC16 deletion inhibited the malignant behavior of NPC cells, and glycolysis inhibition by MUC16 deletion blocked immune escape in NPC cells. E74-like factor 3 (ELF3) bound to the MUC16 promoter promotes the transcription of MUC16. MUC16 overexpression reversed the repressive effect of ELF3 silencing on glycolysis and immune escape in NPC and accelerated tumor growth in vivo. Overexpression of ELF3 in NPC was associated with reduced DNA methylation in its promoter. Our findings revealed the role of the ELF3/MUC16 axis in the immune escape and metabolic reprogramming of NPC, providing potential therapeutic targets for NPC.NEW & NOTEWORTHY We identified the functions of E74-like factor 3 (ELF3) in glycolysis and immune escape of nasopharyngeal carcinoma cells for the first time. As a transcription factor, ELF3 promoted mucin-16 (MUC16) expression by binding to its promoter, leading to the glycolysis-mediated immune escape of nasopharyngeal carcinoma (NPC) cells. Targeting the ELF3/MUC16 axis generates a superior antitumor immune response, which will help establish a novel approach to restore protective antitumor immunity for NPC immunotherapy.
Assuntos
Metilação de DNA , Proteínas de Ligação a DNA , Regulação Neoplásica da Expressão Gênica , Glicólise , Carcinoma Nasofaríngeo , Neoplasias Nasofaríngeas , Fatores de Transcrição , Humanos , Carcinoma Nasofaríngeo/genética , Carcinoma Nasofaríngeo/imunologia , Carcinoma Nasofaríngeo/patologia , Carcinoma Nasofaríngeo/metabolismo , Neoplasias Nasofaríngeas/imunologia , Neoplasias Nasofaríngeas/genética , Neoplasias Nasofaríngeas/patologia , Neoplasias Nasofaríngeas/metabolismo , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Animais , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Linhagem Celular Tumoral , Evasão Tumoral/genética , Camundongos , Proteínas Proto-Oncogênicas c-ets/genética , Proteínas Proto-Oncogênicas c-ets/metabolismo , Camundongos Nus , Masculino , Feminino , Regiões Promotoras Genéticas , Reprogramação Celular/genética , Camundongos Endogâmicos BALB C , Reprogramação MetabólicaRESUMO
Cemiplimab has demonstrated relevant clinical activity in cutaneous squamous cell carcinoma (cSCC) but mechanisms of primary and acquired resistance to immunotherapy are still unknown. We collected clinical data from locally advanced and/or metastatic cSSC patients treated with cemiplimab in two Italian University centers. In addition, gene expression analysis by using Nanostring Technologies platform to evaluate 770 cancer- and immune-related genes on 20 tumor tissue samples (9 responders and 11 non-responders to cemiplimab) was performed. We enrolled 81 patients with a median age of 82 years. After 16.4 months of median follow-up, 12- and 24-months PFS were 53% and 42%, respectively; while 12- and 24-months OS were 71% and 61%, respectively. Treatment was well tolerated. Overall response rate (ORR) was 58%, with a disease control rate (DCR) of 77.8%. The difference between genes expressed in responder versus non-responder patient samples was substantial, particularly for genes involved in immune system regulation. Cemiplimab-resistant tumors were associated with over-expression of CCL-20 and CXCL-8. Cemiplimab confirmed efficacy and safety data in real-life cSCC patients. Overexpression of CCL-20 and CXCL-8 could represent biomarkers of lack of response to immunotherapy.
Assuntos
Anticorpos Monoclonais Humanizados , Carcinoma de Células Escamosas , Resistencia a Medicamentos Antineoplásicos , Interleucina-8 , Neoplasias Cutâneas , Humanos , Anticorpos Monoclonais Humanizados/uso terapêutico , Anticorpos Monoclonais Humanizados/farmacologia , Anticorpos Monoclonais Humanizados/administração & dosagem , Masculino , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Feminino , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/patologia , Idoso , Idoso de 80 Anos ou mais , Resistencia a Medicamentos Antineoplásicos/genética , Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Interleucina-8/genética , Interleucina-8/metabolismo , Evasão Tumoral/efeitos dos fármacos , Evasão Tumoral/genética , Pessoa de Meia-Idade , Inibidores de Checkpoint Imunológico/uso terapêutico , Inibidores de Checkpoint Imunológico/farmacologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Antineoplásicos Imunológicos/uso terapêutico , Antineoplásicos Imunológicos/farmacologiaRESUMO
Immunosuppression characterizes the tumour microenvironment in HCC, and recent studies have implicated RNA-binding proteins (RBPs) in the development of HCC. Here, we conducted a screen and identified RBM12 as a key protein that increased the expression of PD-L1, thereby driving immune evasion in HCC. Furthermore, RBM12 was found to be significantly upregulated in HCC tissues and was associated with a poor prognosis for HCC patients. Through various molecular assays and high-throughput screening, we determined that RBM12 could directly bind to the JAK1 mRNA via its 4th-RRM (RNA recognition motif) domain and recruit EIF4A2 through its 2nd-RRM domain, enhancing the distribution of ribosomes on JAK1 mRNA, which promotes the translation of JAK1 and the subsequent upregulation of its expression. As a result, the activated JAK1/STAT1 pathway transcriptionally upregulates PD-L1 expression, facilitating immune evasion in HCC. In summary, our findings provide insights into the significant contribution of RBM12 to immune evasion in HCC, highlighting its potential as a therapeutic target in the future. This graphical abstract shows that elevated expression of RBM12 in HCC can augment PD-L1-mediated tumour immune evasion by increasing the efficiency of JAK1 mRNA translation.
Assuntos
Antígeno B7-H1 , Carcinoma Hepatocelular , Janus Quinase 1 , Neoplasias Hepáticas , Biossíntese de Proteínas , Proteínas de Ligação a RNA , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Janus Quinase 1/genética , Janus Quinase 1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Proteínas de Ligação a RNA/genética , Proteínas de Ligação a RNA/metabolismo , Regulação Neoplásica da Expressão Gênica , Evasão da Resposta Imune/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Animais , Linhagem Celular Tumoral , Camundongos , Evasão Tumoral/genética , Masculino , Prognóstico , Microambiente Tumoral/imunologia , Microambiente Tumoral/genética , FemininoRESUMO
BACKGROUND: Immune escape is a major obstacle to T-cell-based immunotherapy for cancers such as gastric cancer (GC). Mesoderm-specific transcript (MEST) is a tumor-promoting factor that regulates multiple oncogenic signaling pathways. However, the role of MEST-mediated immune escape is unclear. METHODS: Bioinformatics analysis of MEST expression and enrichment pathways were performed Quantitative reverse transcription PCR (qPCR) or western blot was used to detect the expression of MEST, Src homology region 2-containing protein tyrosine phosphatase 2 (SHP2), Major histocompatibility class I (MHCI)-related genes. Cell function was assessed by Cell Counting Kit (CCK)-8, Transwell, Lactate dehydrogenase (LDH) kit, flow cytometry, enzyme-linked immunosorbent assay (ELISA), and immunohistochemistry (IHC). Xenograft nude mice and immune-reconstructed mice were used to test the effects of different treatments on tumor growth and immune escape in vivo. RESULTS: MEST was upregulated in GC and promoted tumor proliferation, migration, and invasion. Rescue experiments revealed that TNO155 treatment or knockdown of SHP2 promoted the killing ability of CD8+ T cells and the expression of granzyme B (GZMB) and interferon-gamma (IFN-γ), and MEST overexpression reversed the effect. In vivo experiments confirmed that MEST promoted tumor growth, knockdown of MEST inhibited immune escape in GC, and that combination treatment with anti-PD-1 improved anti-tumor activity. CONCLUSION: In this study, we demonstrated that MEST inhibited IFN-γ secretion from CD8+ T cells by up-regulating SHP2, thereby downregulating MHCI expression in GC cells to promote immune escape and providing a new T cell-based therapeutic potential for GC.
Assuntos
Regulação para Baixo , Camundongos Nus , Proteína Tirosina Fosfatase não Receptora Tipo 11 , Neoplasias Gástricas , Evasão Tumoral , Animais , Feminino , Humanos , Masculino , Camundongos , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/metabolismo , Linhagem Celular Tumoral , Proliferação de Células , Regulação Neoplásica da Expressão Gênica , Antígenos de Histocompatibilidade Classe I/imunologia , Antígenos de Histocompatibilidade Classe I/genética , Antígenos de Histocompatibilidade Classe I/metabolismo , Camundongos Endogâmicos BALB C , Proteína Tirosina Fosfatase não Receptora Tipo 11/genética , Proteína Tirosina Fosfatase não Receptora Tipo 11/metabolismo , Proteína Tirosina Fosfatase não Receptora Tipo 11/imunologia , Neoplasias Gástricas/imunologia , Neoplasias Gástricas/genética , Neoplasias Gástricas/patologia , Evasão Tumoral/genéticaRESUMO
This study investigates the role of M2-exo-mediated HOXC13-AS in laryngeal squamous cell carcinoma (LSCC) by examining its transmission to tumor microenvironment (TME) macrophages. Exosomes from M2 macrophages were isolated and characterized using transmission electron microscopy, nanoparticle tracer analysis and western blot. Expression of HOXC13-AS, miR-485-5p, IGF2BP2, and PD-L1 was analyzed. Different interventions on LSCC cell function and immune escape were detected using molecular biological techniques. The study found that elevated HOXC13-AS were present in LSCC, and M2-exo expression was significantly increased in LSCC cells. Silencing HOXC13-AS in M2-exo inhibited LSCC malignant progression and immune escape in vivo and in vitro. M2-exo-mediated HOXC13-AS also regulated IGF2BP2 expression, impacting cellular biological function and immune escape process. The study concludes that M2-exo-mediated HOXC13-AS promotes LSCC malignancy and immune escape.
Assuntos
Exossomos , Proteínas de Homeodomínio , Neoplasias Laríngeas , Macrófagos , RNA Longo não Codificante , Microambiente Tumoral , Animais , Humanos , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Linhagem Celular Tumoral , Exossomos/metabolismo , Exossomos/genética , Regulação Neoplásica da Expressão Gênica , Proteínas de Homeodomínio/genética , Proteínas de Homeodomínio/metabolismo , Neoplasias Laríngeas/imunologia , Neoplasias Laríngeas/genética , Neoplasias Laríngeas/patologia , Macrófagos/imunologia , Camundongos Nus , MicroRNAs/genética , MicroRNAs/metabolismo , Proteínas de Ligação a RNA/metabolismo , Proteínas de Ligação a RNA/genética , Evasão Tumoral/genética , Microambiente Tumoral/imunologia , RNA Longo não Codificante/genéticaRESUMO
BACKGROUND: Long non-coding RNAs (LncRNAs) have been implicated as critical regulators of cancer tumorigenesis and progression. However, their functions and molecular mechanisms in colorectal cancer (CRC) still remain to be further elucidated. METHODS: LINC00460 was identified by differential analysis between human CRC and normal tissues and verified by in situ hybridization (ISH) and qRT-PCR. We investigated the biological functions of LINC00460 in CRC by in vitro and in vivo experiments. We predicted the mechanism and downstream functional molecules of LINC00460 by bioinformatics analysis, and confirmed them by dual luciferase reporter gene assay, RNA immunoprecipitation (RIP), RNA pull-down, etc. RESULTS: LINC00460 was found to be significantly overexpressed in CRC and associated with poor prognosis. Overexpression of LINC00460 promoted CRC cell immune escape and remodeled a suppressive tumor immune microenvironment, thereby promoting CRC proliferation and metastasis. Mechanistic studies showed that LINC00460 served as a molecular sponge for miR-186-3p, and then promoted the expressions of MYC, CD47 and PD-L1 to facilitate CRC cell immune escape. We also demonstrated that MYC upregulated LINC00460 expression at the transcriptional level and formed a positive feedback loop. CONCLUSIONS: The LINC00460/miR-186-3p/MYC feedback loop promotes CRC cell immune escape and subsequently facilitates CRC proliferation and metastasis. Our findings provide novel insight into LINC00460 as a CRC immune regulator, and provide a potential therapeutic target for CRC patients.
Assuntos
Antígeno B7-H1 , Antígeno CD47 , Neoplasias Colorretais , MicroRNAs , RNA Longo não Codificante , Humanos , Neoplasias Colorretais/genética , Neoplasias Colorretais/patologia , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/imunologia , MicroRNAs/genética , Antígeno CD47/metabolismo , Antígeno CD47/genética , RNA Longo não Codificante/genética , RNA Longo não Codificante/metabolismo , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Animais , Regulação Neoplásica da Expressão Gênica , Linhagem Celular Tumoral , Evasão Tumoral/genética , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas c-myc/genética , Masculino , Feminino , Proliferação de Células , Retroalimentação Fisiológica , Prognóstico , Camundongos NusRESUMO
Gallbladder cancer (GBC) is the most common malignant tumor of the biliary system, with poor response to current treatments. Abnormal alternative splicing has been associated with the development of a variety of tumors. Combining the GEO database and GBC mRNA-seq analysis, it is found high expression of the splicing factor polypyrimidine region- binding protein 3 (PTBP3) in GBC. Multi-omics analysis revealed that PTBP3 promoted exon skipping of interleukin-18 (IL-18), resulting in the expression of ΔIL-18, an isoform specifically expressed in tumors. That ΔIL-18 promotes GBC immune escape by down-regulating FBXO38 transcription levels in CD8+T cells to reduce PD-1 ubiquitin-mediated degradation is revealed. Using a HuPBMC mouse model, the role of PTBP3 and ΔIL-18 in promoting GBC growth is confirmed, and showed that an antisense oligonucleotide that blocked ΔIL-18 production displayed anti-tumor activity. Furthermore, that the H3K36me3 promotes exon skipping of IL-18 by recruiting PTBP3 via MRG15 is demonstrated, thereby coupling the processes of IL-18 transcription and alternative splicing. Interestingly, it is also found that the H3K36 methyltransferase SETD2 binds to hnRNPL, thereby interfering with PTBP3 binding to IL-18 pre-mRNA. Overall, this study provides new insights into how aberrant alternative splicing mechanisms affect immune escape, and provides potential new perspectives for improving GBC immunotherapy.
Assuntos
Éxons , Neoplasias da Vesícula Biliar , Interleucina-18 , Proteína de Ligação a Regiões Ricas em Polipirimidinas , Animais , Feminino , Humanos , Camundongos , Processamento Alternativo/genética , Linhagem Celular Tumoral , Modelos Animais de Doenças , Éxons/genética , Neoplasias da Vesícula Biliar/genética , Neoplasias da Vesícula Biliar/imunologia , Interleucina-18/genética , Interleucina-18/metabolismo , Interleucina-18/imunologia , Proteína de Ligação a Regiões Ricas em Polipirimidinas/genética , Proteína de Ligação a Regiões Ricas em Polipirimidinas/metabolismo , Proteína de Ligação a Regiões Ricas em Polipirimidinas/imunologia , Evasão Tumoral/genética , Evasão Tumoral/imunologiaAssuntos
Linfoma Difuso de Grandes Células B , Mutação , Recidiva Local de Neoplasia , Humanos , Linfoma Difuso de Grandes Células B/genética , Linfoma Difuso de Grandes Células B/patologia , Linfoma Difuso de Grandes Células B/imunologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/patologia , Evasão Tumoral/genética , PrognósticoRESUMO
Programmed death-ligand 1 (PD-L1) is overexpressed in multiple cancers and critical for their immune escape. It has previously shown that the nuclear coactivator SRC-1 promoted colorectal cancer (CRC) progression by enhancing CRC cell viability, yet its role in CRC immune escape is unclear. Here, we demonstrate that SRC-1 is positively correlated with PD-L1 in human CRC specimens. SRC-1 deficiency significantly inhibits PD-L1 expression in CRC cells and retards murine CRC growth in subcutaneous grafts by enhancing CRC immune escape via increasing tumor infiltration of CD8+ T cells. Genetic ablation of SRC-1 in mice also decreases PD-L1 expression in AOM/DSS-induced murine CRC. These results suggest that tumor-derived SRC-1 promotes CRC immune escape by enhancing PD-L1 expression. Mechanistically, SRC-1 activated JAK-STAT signaling by inhibiting SOCS1 expression and coactivated STAT3 and IRF1 to enhance PD-L1 transcription as well as stabilized PD-L1 protein by inhibiting proteasome-dependent degradation mediated by speckle type POZ protein (SPOP). Pharmacological inhibition of SRC-1 improved the antitumor effect of PD-L1 antibody in both subcutaneous graft and AOM/DSS-induced murine CRC models. Taken together, these findings highlight a crucial role of SRC-1 in regulating PD-L1 expression and targeting SRC-1 in combination with PD-L1 antibody immunotherapy may be an attractive strategy for CRC treatment.
Assuntos
Antígeno B7-H1 , Neoplasias Colorretais , Modelos Animais de Doenças , Coativador 1 de Receptor Nuclear , Evasão Tumoral , Neoplasias Colorretais/genética , Neoplasias Colorretais/metabolismo , Neoplasias Colorretais/imunologia , Animais , Camundongos , Antígeno B7-H1/metabolismo , Antígeno B7-H1/genética , Antígeno B7-H1/imunologia , Humanos , Coativador 1 de Receptor Nuclear/genética , Coativador 1 de Receptor Nuclear/metabolismo , Evasão Tumoral/genética , Evasão Tumoral/imunologia , Estabilidade Proteica , Linhagem Celular Tumoral , Camundongos Endogâmicos C57BLRESUMO
BACKGROUND: Neuroblastoma (NB) is the most prevalent and deadliest pediatric solid tumor. With of over 50% of high-risk neuroblastoma cases relapse, the imperative for novel drug targets and therapeutic strategies is accentuated. In neuroblastoma, the existence of tumor-associated macrophages (TAMs) correlates with an unfavorable patient prognosis. However, the clinical relevance and prognostic implications of regulatory genes linked to TAMs infiltration in neuroblastoma remain unclear, and further study is required. METHODS: We conducted a comprehensive analysis utilizing transcriptome expression profiles from three primary datasets associated with neuroblastoma (GSE45547, GSE49710, TARGET) to identify hub genes implicated in immune evasion within neuroblastoma. Subsequently, we utilized single-cell RNA sequencing analysis on 17 clinical neuroblastoma samples to investigate the expression and distribution of these hub genes, leading to the identification of TNFAIP3. The above three public databases were merged to allowed for the validation of TNFAIP3's molecular functions through GO and KEGG analysis. Furthermore, we assessed TNFAIP3's correlation with immune infiltration and its potential immunotherapeutic impact by multiple algorithms. Our single-cell transcriptome data revealed the role of TNFAIP3 in macrophage polarization. Finally, preliminary experimental verifications to confirm the biological functions of TNFAIP3-mediated TAMs in NB. RESULTS: A total of 6 genes related to immune evasion were screened and we found that TNFAIP3 exhibited notably higher expression in macrophages than other immune cell types, based on the scRNA-sequencing data. GO and KEGG analysis showed that low expression of TNFAIP3 significantly correlated with the activation of multiple oncogenic pathways as well as immune-related pathways. Then validation affirmed that individuals within the TNFAIP3 high-expression cohort could potentially derive greater advantages from immunotherapeutic interventions, alongside exhibiting heightened immune responsiveness. Deciphering the pseudotime trajectory of macrophages, we revealed the potential of TNFAIP3 in inducing the polarization of macrophages towards the M1 phenotype. Finally, we confirmed that patients in the TNFAIP3 high expression group might benefit more from immunotherapy or chemotherapy as substantiated by RT-qPCR and immunofluorescence examinations. Moreover, the role of TNFAIP3 in macrophage polarization was validated. Preliminary experiment showed that TNFAIP3-mediated TAMs inhibit the proliferation, migration and invasion capabilities of NB cells. CONCLUSIONS: Our results suggest that TNFAIP3 was first identified as a promising biomarker for immunotherapy and potential molecular target in NB. Besides, the presence of TNFAIP3 within TAMs may offer a novel therapeutic strategy for NB.
Assuntos
Biomarcadores Tumorais , Neuroblastoma , Proteína 3 Induzida por Fator de Necrose Tumoral alfa , Humanos , Neuroblastoma/genética , Neuroblastoma/imunologia , Proteína 3 Induzida por Fator de Necrose Tumoral alfa/genética , Biomarcadores Tumorais/genética , Prognóstico , Perfilação da Expressão Gênica , Transcriptoma , Macrófagos Associados a Tumor/imunologia , Evasão Tumoral/genética , Regulação Neoplásica da Expressão GênicaRESUMO
Immune checkpoint inhibitors have produced encouraging results in cancer patients. However, the majority of ß-catenin-mutated tumors have been described as lacking immune infiltrates and resistant to immunotherapy. The mechanisms by which oncogenic ß-catenin affects immune surveillance remain unclear. Herein, we highlighted the involvement of ß-catenin in the regulation of the exosomal pathway and, by extension, in immune/cancer cell communication in hepatocellular carcinoma (HCC). We showed that mutated ß-catenin represses expression of SDC4 and RAB27A, two main actors in exosome biogenesis, in both liver cancer cell lines and HCC patient samples. Using nanoparticle tracking analysis and live-cell imaging, we further demonstrated that activated ß-catenin represses exosome release. Then, we demonstrated in 3D spheroid models that activation of ß-catenin promotes a decrease in immune cell infiltration through a defect in exosome secretion. Taken together, our results provide the first evidence that oncogenic ß-catenin plays a key role in exosome biogenesis. Our study gives new insight into the impact of ß-catenin mutations on tumor microenvironment remodeling, which could lead to the development of new strategies to enhance immunotherapeutic response.
Assuntos
Carcinoma Hepatocelular , Exossomos , Neoplasias Hepáticas , Evasão Tumoral , beta Catenina , Proteínas rab27 de Ligação ao GTP , Humanos , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/imunologia , Carcinoma Hepatocelular/metabolismo , Carcinoma Hepatocelular/patologia , Exossomos/metabolismo , Exossomos/genética , beta Catenina/metabolismo , beta Catenina/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/imunologia , Neoplasias Hepáticas/metabolismo , Neoplasias Hepáticas/patologia , Linhagem Celular Tumoral , Evasão Tumoral/genética , Proteínas rab27 de Ligação ao GTP/metabolismo , Proteínas rab27 de Ligação ao GTP/genética , Microambiente Tumoral/imunologia , Mutação , Regulação Neoplásica da Expressão GênicaAssuntos
Neoplasias , Evasão Tumoral , Humanos , Neoplasias/genética , Neoplasias/imunologia , Evasão Tumoral/genética , AnimaisRESUMO
Inhibition of a mutated metabolic enzyme puts the sting back in antitumor immunity.