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1.
PLoS One ; 19(5): e0303171, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38768113

RESUMEN

Tumor microenvironment (TME) is a complex dynamic system with many tumor-interacting components including tumor-infiltrating leukocytes (TILs), cancer associated fibroblasts, blood vessels, and other stromal constituents. It intrinsically affects tumor development and pharmacology of oncology therapeutics, particularly immune-oncology (IO) treatments. Accurate measurement of TME is therefore of great importance for understanding the tumor immunity, identifying IO treatment mechanisms, developing predictive biomarkers, and ultimately, improving the treatment of cancer. Here, we introduce a mouse-IO NGS-based (NGSmIO) assay for accurately detecting and quantifying the mRNA expression of 1080 TME related genes in mouse tumor models. The NGSmIO panel was shown to be superior to the commonly used microarray approach by hosting 300 more relevant genes to better characterize various lineage of immune cells, exhibits improved mRNA and protein expression correlation to flow cytometry, shows stronger correlation with mRNA expression than RNAseq with 10x higher sequencing depth, and demonstrates higher sensitivity in measuring low-expressed genes. We describe two studies; firstly, detecting the pharmacodynamic change of interferon-γ expression levels upon anti-PD-1: anti-CD4 combination treatment in MC38 and Hepa 1-6 tumors; and secondly, benchmarking baseline TILs in 14 syngeneic tumors using transcript level expression of lineage specific genes, which demonstrate effective and robust applications of the NGSmIO panel.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Microambiente Tumoral , Animales , Ratones , Microambiente Tumoral/inmunología , Secuenciación de Nucleótidos de Alto Rendimiento/métodos , Interferón gamma/genética , Interferón gamma/metabolismo , Línea Celular Tumoral , Regulación Neoplásica de la Expresión Génica , Modelos Animales de Enfermedad , Ratones Endogámicos C57BL , ARN Mensajero/genética , Receptor de Muerte Celular Programada 1/genética , Receptor de Muerte Celular Programada 1/metabolismo , Neoplasias/genética , Neoplasias/inmunología , Femenino , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Perfilación de la Expresión Génica/métodos
2.
Cell Mol Biol Lett ; 29(1): 77, 2024 May 20.
Artículo en Inglés | MEDLINE | ID: mdl-38769475

RESUMEN

BACKGROUND: Tumor-associated macrophages (TAMs) significantly influence the progression, metastasis, and recurrence of esophageal squamous cell carcinoma (ESCC). The aberrant expression of long noncoding RNAs (lncRNAs) in ESCC has been established, yet the role of lncRNAs in TAM reprogramming during ESCC progression remains largely unexplored. METHODS: ESCC TAM-related lncRNAs were identified by intersecting differentially expressed lncRNAs with immune-related lncRNAs and performing immune cell infiltration analysis. The expression profile and clinical relevance of LINC00330 were examined using the TCGA database and clinical samples. The LINC00330 overexpression and interference sequences were constructed to evaluate the effect of LINC00330 on ESCC progression. Single-cell sequencing data, CIBERSORTx, and GEPIA were utilized to analyze immune cell infiltration within the ESCC tumor microenvironment and to assess the correlation between LINC00330 and TAM infiltration. ESCC-macrophage coculture experiments were conducted to investigate the influence of LINC00330 on TAM reprogramming and its subsequent effect on ESCC progression. The interaction between LINC00330 and C-C motif ligand 2 (CCL2) was confirmed through transcriptomic sequencing, subcellular localization analysis, RNA pulldown, silver staining, RNA immunoprecipitation, and other experiments. RESULTS: LINC00330 is significantly downregulated in ESCC tissues and strongly associated with poor patient outcomes. Overexpression of LINC00330 inhibits ESCC progression, including proliferation, invasion, epithelial-mesenchymal transition, and tumorigenicity in vivo. LINC00330 promotes TAM reprogramming, and LINC00330-mediated TAM reprogramming inhibits ESCC progression. LINC00330 binds to the CCL2 protein and inhibits the expression of CCL2 and downstream signaling pathways. CCL2 is critical for LINC00330-mediated TAM reprogramming and ESCC progression. CONCLUSIONS: LINC00330 inhibited ESCC progression by disrupting the CCL2/CCR2 axis and its downstream signaling pathways in an autocrine fashion; and by impeding CCL2-mediated TAM reprogramming in a paracrine manner. The new mechanism of TAM reprogramming mediated by the LINC00330/CCL2 axis may provide potential strategies for targeted and immunocombination therapies for patients with ESCC.


Asunto(s)
Quimiocina CCL2 , Progresión de la Enfermedad , Neoplasias Esofágicas , Carcinoma de Células Escamosas de Esófago , Regulación Neoplásica de la Expresión Génica , ARN Largo no Codificante , Microambiente Tumoral , Macrófagos Asociados a Tumores , ARN Largo no Codificante/genética , ARN Largo no Codificante/metabolismo , Humanos , Quimiocina CCL2/genética , Quimiocina CCL2/metabolismo , Carcinoma de Células Escamosas de Esófago/genética , Carcinoma de Células Escamosas de Esófago/patología , Carcinoma de Células Escamosas de Esófago/metabolismo , Línea Celular Tumoral , Microambiente Tumoral/genética , Macrófagos Asociados a Tumores/metabolismo , Neoplasias Esofágicas/genética , Neoplasias Esofágicas/patología , Neoplasias Esofágicas/metabolismo , Animales , Ratones , Femenino , Proliferación Celular/genética
3.
Proc Natl Acad Sci U S A ; 121(22): e2322479121, 2024 May 28.
Artículo en Inglés | MEDLINE | ID: mdl-38771871

RESUMEN

The significance of biochemical cues in the tumor immune microenvironment in affecting cancer metastasis is well established, but the role of physical factors in the microenvironment remains largely unexplored. In this article, we investigated how the mechanical interaction between cancer cells and immune cells, mediated by extracellular matrix (ECM), influences immune escape of cancer cells. We focus on the mechanical regulation of macrophages' targeting ability on two distinct types of colorectal carcinoma (CRC) cells with different metastatic potentials. Our results show that macrophages can effectively target CRC cells with low metastatic potential, due to the strong contraction exhibited by the cancer cells on the ECM, and that cancer cells with high metastatic potential demonstrated weakened contractions on the ECM and can thus evade macrophage attack to achieve immune escape. Our findings regarding the intricate mechanical interactions between immune cells and cancer cells can serve as a crucial reference for further exploration of cancer immunotherapy strategies.


Asunto(s)
Neoplasias Colorrectales , Matriz Extracelular , Macrófagos , Escape del Tumor , Microambiente Tumoral , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Macrófagos/inmunología , Humanos , Microambiente Tumoral/inmunología , Matriz Extracelular/metabolismo , Matriz Extracelular/inmunología , Línea Celular Tumoral , Metástasis de la Neoplasia , Animales , Ratones , Comunicación Celular/inmunología
4.
JCI Insight ; 9(10)2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38775157

RESUMEN

Redundant tumor microenvironment (TME) immunosuppressive mechanisms and epigenetic maintenance of terminal T cell exhaustion greatly hinder functional antitumor immune responses in chronic lymphocytic leukemia (CLL). Bromodomain and extraterminal (BET) proteins regulate key pathways contributing to CLL pathogenesis and TME interactions, including T cell function and differentiation. Herein, we report that blocking BET protein function alleviates immunosuppressive networks in the CLL TME and repairs inherent CLL T cell defects. The pan-BET inhibitor OPN-51107 reduced exhaustion-associated cell signatures resulting in improved T cell proliferation and effector function in the Eµ-TCL1 splenic TME. Following BET inhibition (BET-i), TME T cells coexpressed significantly fewer inhibitory receptors (IRs) (e.g., PD-1, CD160, CD244, LAG3, VISTA). Complementary results were witnessed in primary CLL cultures, wherein OPN-51107 exerted proinflammatory effects on T cells, regardless of leukemic cell burden. BET-i additionally promotes a progenitor T cell phenotype through reduced expression of transcription factors that maintain terminal differentiation and increased expression of TCF-1, at least in part through altered chromatin accessibility. Moreover, direct T cell effects of BET-i were unmatched by common targeted therapies in CLL. This study demonstrates the immunomodulatory action of BET-i on CLL T cells and supports the inclusion of BET inhibitors in the management of CLL to alleviate terminal T cell dysfunction and potentially enhance tumoricidal T cell activity.


Asunto(s)
Leucemia Linfocítica Crónica de Células B , Linfocitos T , Microambiente Tumoral , Leucemia Linfocítica Crónica de Células B/inmunología , Leucemia Linfocítica Crónica de Células B/tratamiento farmacológico , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de los fármacos , Humanos , Animales , Ratones , Linfocitos T/inmunología , Linfocitos T/efectos de los fármacos , Linfocitos T/metabolismo , Factores de Transcripción/metabolismo , Factores de Transcripción/genética , Factor Nuclear 1-alfa del Hepatocito/metabolismo , Factor Nuclear 1-alfa del Hepatocito/genética , Proliferación Celular/efectos de los fármacos , Proteínas que Contienen Bromodominio , Proteínas
5.
JCI Insight ; 9(10)2024 May 22.
Artículo en Inglés | MEDLINE | ID: mdl-38775151

RESUMEN

Because cancer cells have a genetically unstable nature, they give rise to genetically different variant subclones inside a single tumor. Understanding cancer heterogeneity and subclone characteristics is crucial for developing more efficacious therapies. Oral squamous cell carcinoma (OSCC) is characterized by high heterogeneity and plasticity. On the other hand, CX3C motif ligand 1 (CX3CL1) is a double-faced chemokine with anti- and pro-tumor functions. Our study reported that CX3CL1 functioned differently in tumors with different cancer phenotypes, both in vivo and in vitro. Mouse OSCC 1 (MOC1) and MOC2 cells responded similarly to CX3CL1 in vitro. However, in vivo, CX3CL1 increased keratinization in indolent MOC1 cancer, while CX3CL1 promoted cervical lymphatic metastasis in aggressive MOC2 cancer. These outcomes were due to double-faced CX3CL1 effects on different immune microenvironments indolent and aggressive cancer created. Furthermore, we established that CX3CL1 promoted cancer metastasis via the lymphatic pathway by stimulating lymphangiogenesis and transendothelial migration of lymph-circulating tumor cells. CX3CL1 enrichment in lymphatic metastasis tissues was observed in aggressive murine and human cell lines. OSCC patient samples with CX3CL1 enrichment exhibited a strong correlation with lower overall survival rates and higher recurrence and distant metastasis rates. In conclusion, CX3CL1 is a pivotal factor that stimulates the metastasis of aggressive cancer subclones within the heterogeneous tumors to metastasize, and our study demonstrates the prognostic value of CX3CL1 enrichment in long-term monitoring in OSCC.


Asunto(s)
Carcinoma de Células Escamosas , Quimiocina CX3CL1 , Linfangiogénesis , Metástasis Linfática , Neoplasias de la Boca , Quimiocina CX3CL1/metabolismo , Quimiocina CX3CL1/genética , Animales , Neoplasias de la Boca/patología , Neoplasias de la Boca/genética , Neoplasias de la Boca/metabolismo , Ratones , Linfangiogénesis/genética , Humanos , Línea Celular Tumoral , Metástasis Linfática/patología , Carcinoma de Células Escamosas/patología , Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/metabolismo , Femenino , Microambiente Tumoral/inmunología , Masculino
6.
Sci Adv ; 10(19): eadm9561, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38718119

RESUMEN

Lactic acid (LA) accumulation in the tumor microenvironment poses notable challenges to effective tumor immunotherapy. Here, an intelligent tumor treatment microrobot based on the unique physiological structure and metabolic characteristics of Veillonella atypica (VA) is proposed by loading Staphylococcus aureus cell membrane-coating BaTiO3 nanocubes (SAM@BTO) on the surface of VA cells (VA-SAM@BTO) via click chemical reaction. Following oral administration, VA-SAM@BTO accurately targeted orthotopic colorectal cancer through inflammatory targeting of SAM and hypoxic targeting of VA. Under in vitro ultrasonic stimulation, BTO catalyzed two reduction reactions (O2 → •O2- and CO2 → CO) and three oxidation reactions (H2O → •OH, GSH → GSSG, and LA → PA) simultaneously, effectively inducing immunogenic death of tumor cells. BTO catalyzed the oxidative coupling of VA cells metabolized LA, effectively disrupting the immunosuppressive microenvironment, improving dendritic cell maturation and macrophage M1 polarization, and increasing effector T cell proportions while decreasing regulatory T cell numbers, which facilitates synergetic catalysis and immunotherapy.


Asunto(s)
Neoplasias Colorrectales , Inmunoterapia , Microambiente Tumoral , Neoplasias Colorrectales/terapia , Neoplasias Colorrectales/inmunología , Neoplasias Colorrectales/patología , Inmunoterapia/métodos , Animales , Ratones , Humanos , Catálisis , Línea Celular Tumoral , Nanoestructuras/química , Materiales Biomiméticos/química , Administración Oral , Titanio/química , Biomimética/métodos , Ácido Láctico/química , Células Dendríticas/inmunología , Células Dendríticas/metabolismo , Compuestos de Bario
7.
Front Immunol ; 15: 1372692, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38720884

RESUMEN

Background: The tertiary lymphatic structure (TLS) is an important component of the tumor immune microenvironment and has important significance in patient prognosis and response to immune therapy. However, the underlying mechanism of TLS in soft tissue sarcoma remains unclear. Methods: A total of 256 RNAseq and 7 single-cell sequencing samples were collected from TCGA-SARC and GSE212527 cohorts. Based on published TLS-related gene sets, four TLS scores were established by GSVA algorithm. The immune cell infiltration was calculated via TIMER2.0 and "MCPcounter" algorithms. In addition, the univariate, LASSO, and multivariate-Cox analyses were used to select TLS-related and prognosis-significant hub genes. Single-cell sequencing dataset, clinical immunohistochemical, and cell experiments were utilized to validate the hub genes. Results: In this study, four TLS-related scores were identified, and the total-gene TLS score more accurately reflected the infiltration level of TLS in STS. We further established two hub genes (DUSP9 and TNFSF14) prognosis markers and risk scores associated with soft tissue sarcoma prognosis and immune therapy response. Flow cytometry analysis showed that the amount of CD3, CD8, CD19, and CD11c positive immune cell infiltration in the tumor tissue dedifferentiated liposarcoma patients was significantly higher than that of liposarcoma patients. Cytological experiments showed that soft tissue sarcoma cell lines overexpressing TNFSF14 could inhibit the proliferation and migration of sarcoma cells. Conclusion: This study systematically explored the TLS and related genes from the perspectives of bioinformatics, clinical features and cytology experiments. The total-gene TLS score, risk score and TNFSF14 hub gene may be useful biomarkers for predicting the prognosis and immunotherapy efficacy of soft tissue sarcoma.


Asunto(s)
Biomarcadores de Tumor , Inmunoterapia , Sarcoma , Microambiente Tumoral , Humanos , Sarcoma/genética , Sarcoma/terapia , Sarcoma/inmunología , Sarcoma/diagnóstico , Biomarcadores de Tumor/genética , Pronóstico , Inmunoterapia/métodos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Regulación Neoplásica de la Expresión Génica , Femenino , Masculino , Miembro 14 de la Superfamilia de Ligandos de Factores de Necrosis Tumoral/genética , Perfilación de la Expresión Génica , Análisis de la Célula Individual
8.
Front Immunol ; 15: 1310376, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38720887

RESUMEN

Introduction: Hypopharyngeal squamous cell carcinoma (HSCC) is one of the malignant tumors with the worst prognosis in head and neck cancers. The transformation from normal tissue through low-grade and high-grade intraepithelial neoplasia to cancerous tissue in HSCC is typically viewed as a progressive pathological sequence typical of tumorigenesis. Nonetheless, the alterations in diverse cell clusters within the tissue microenvironment (TME) throughout tumorigenesis and their impact on the development of HSCC are yet to be fully understood. Methods: We employed single-cell RNA sequencing and TCR/BCR sequencing to sequence 60,854 cells from nine tissue samples representing different stages during the progression of HSCC. This allowed us to construct dynamic transcriptomic maps of cells in diverse TME across various disease stages, and experimentally validated the key molecules within it. Results: We delineated the heterogeneity among tumor cells, immune cells (including T cells, B cells, and myeloid cells), and stromal cells (such as fibroblasts and endothelial cells) during the tumorigenesis of HSCC. We uncovered the alterations in function and state of distinct cell clusters at different stages of tumor development and identified specific clusters closely associated with the tumorigenesis of HSCC. Consequently, we discovered molecules like MAGEA3 and MMP3, pivotal for the diagnosis and treatment of HSCC. Discussion: Our research sheds light on the dynamic alterations within the TME during the tumorigenesis of HSCC, which will help to understand its mechanism of canceration, identify early diagnostic markers, and discover new therapeutic targets.


Asunto(s)
Neoplasias Hipofaríngeas , Análisis de la Célula Individual , Microambiente Tumoral , Humanos , Neoplasias Hipofaríngeas/genética , Neoplasias Hipofaríngeas/patología , Neoplasias Hipofaríngeas/inmunología , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Receptores de Antígenos de Linfocitos T/genética , Receptores de Antígenos de Linfocitos T/metabolismo , Receptores de Antígenos de Linfocitos B/genética , Receptores de Antígenos de Linfocitos B/metabolismo , Carcinogénesis/genética , Análisis de Secuencia de ARN , Transcriptoma , Biomarcadores de Tumor/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/genética , Carcinoma de Células Escamosas de Cabeza y Cuello/inmunología , Carcinoma de Células Escamosas de Cabeza y Cuello/patología , Regulación Neoplásica de la Expresión Génica , Masculino
9.
Front Immunol ; 15: 1373497, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38720889

RESUMEN

Introduction: Intraoperative radiation therapy (IORT) delivers a single accelerated radiation dose to the breast tumor bed during breast-conserving surgery (BCS). The synergistic biologic effects of simultaneous surgery and radiation remain unclear. This study explores the cellular and molecular changes induced by IORT in the tumor microenvironment and its impact on the immune response modulation. Methods: Patients with hormone receptor (HR)-positive/HER2-negative, ductal carcinoma in situ (DCIS), or early-stage invasive breast carcinoma undergoing BCS with margin re-excision were included. Histopathological evaluation and RNA-sequencing in the re-excision tissue were compared between patients with IORT (n=11) vs. non-IORT (n=11). Results: Squamous metaplasia with atypia was exclusively identified in IORT specimens (63.6%, p=0.004), mimicking DCIS. We then identified 1,662 differentially expressed genes (875 upregulated and 787 downregulated) between IORT and non-IORT samples. Gene ontology analyses showed that IORT was associated with the enrichment of several immune response pathways, such as inflammatory response, granulocyte activation, and T-cell activation (p<0.001). When only considering normal tissue from both cohorts, IORT was associated with intrinsic apoptotic signaling, response to gamma radiation, and positive regulation of programmed cell death (p<0.001). Using the xCell algorithm, we inferred a higher abundance of γδ T-cells, dendritic cells, and monocytes in the IORT samples. Conclusion: IORT induces histological changes, including squamous metaplasia with atypia, and elicits molecular alterations associated with immune response and intrinsic apoptotic pathways. The increased abundance of immune-related components in breast tissue exposed to IORT suggests a potential shift towards active immunogenicity, particularly immune-desert tumors like HR-positive/HER2-negative breast cancer.


Asunto(s)
Neoplasias de la Mama , Inmunomodulación , Cuidados Intraoperatorios , Mastectomía Segmentaria , Microambiente Tumoral , Humanos , Femenino , Neoplasias de la Mama/radioterapia , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/patología , Persona de Mediana Edad , Microambiente Tumoral/inmunología , Microambiente Tumoral/efectos de la radiación , Inmunomodulación/efectos de la radiación , Anciano , Adulto , Terapia Combinada
10.
J Mol Neurosci ; 74(2): 52, 2024 May 10.
Artículo en Inglés | MEDLINE | ID: mdl-38724832

RESUMEN

Treatment of glioblastoma multiforme (GBM) remains challenging. Unraveling the orchestration of glutamine metabolism may provide a novel viewpoint on GBM therapy. The study presented a full and comprehensive comprehending of the glutamine metabolism atlas and heterogeneity in GBM for facilitating the development of a more effective therapeutic choice. Transcriptome data from large GBM cohorts were integrated in this study. A glutamine metabolism-based classification was established through consensus clustering approach, and a classifier by LASSO analysis was defined for differentiating the classification. Prognosis, signaling pathway activity, tumor microenvironment, and responses to immune checkpoint blockade (ICB) and small molecular drugs were characterized in each cluster. A combinational therapy of glutaminase inhibitor CB839 with dihydroartemisinin (DHA) was proposed, and the influence on glutamine metabolism, apoptosis, reactive oxygen species (ROS), and migration was measured in U251 and U373 cells. We discovered that GBM presented heterogeneous glutamine metabolism-based clusters, with unique survival outcomes, activity of signaling pathways, tumor microenvironment, and responses to ICB and small molecular compounds. In addition, the classifier could accurately differentiate the two clusters. Strikingly, the combinational therapy of CB839 with DHA synergistically attenuated glutamine metabolism, triggered apoptosis and ROS accumulation, and impaired migrative capacity in GBM cells, demonstrating the excellent preclinical efficacy. Altogether, our findings unveil the glutamine metabolism heterogeneity in GBM and propose an innovative combination therapy of CB839 with DHA for this malignant disease.


Asunto(s)
Artemisininas , Neoplasias Encefálicas , Glioblastoma , Glutamina , Glioblastoma/metabolismo , Glioblastoma/tratamiento farmacológico , Humanos , Glutamina/metabolismo , Línea Celular Tumoral , Neoplasias Encefálicas/metabolismo , Neoplasias Encefálicas/tratamiento farmacológico , Artemisininas/uso terapéutico , Artemisininas/farmacología , Especies Reactivas de Oxígeno/metabolismo , Glutaminasa/metabolismo , Glutaminasa/antagonistas & inhibidores , Microambiente Tumoral , Apoptosis , Tiadiazoles/farmacología , Tiadiazoles/uso terapéutico , Movimiento Celular , Bencenoacetamidas/farmacología , Bencenoacetamidas/uso terapéutico , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapéutico , Protocolos de Quimioterapia Combinada Antineoplásica/farmacología
12.
Front Immunol ; 15: 1409021, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38751430

RESUMEN

Chimeric antigen receptor-T (CAR-T) cell therapy has made remarkable strides in treating hematological malignancies. However, the widespread adoption of CAR-T cell therapy is hindered by several challenges. These include concerns about the long-term and complex manufacturing process, as well as efficacy factors such as tumor antigen escape, CAR-T cell exhaustion, and the immunosuppressive tumor microenvironment. Additionally, safety issues like the risk of secondary cancers post-treatment, on-target off-tumor toxicity, and immune effector responses triggered by CAR-T cells are significant considerations. To address these obstacles, researchers have explored various strategies, including allogeneic universal CAR-T cell development, infusion of non-activated quiescent T cells within a 24-hour period, and in vivo induction of CAR-T cells. This review comprehensively examines the clinical challenges of CAR-T cell therapy and outlines strategies to overcome them, aiming to chart pathways beyond its current Achilles heels.


Asunto(s)
Inmunoterapia Adoptiva , Receptores Quiméricos de Antígenos , Linfocitos T , Humanos , Inmunoterapia Adoptiva/métodos , Inmunoterapia Adoptiva/efectos adversos , Receptores Quiméricos de Antígenos/inmunología , Receptores Quiméricos de Antígenos/genética , Animales , Linfocitos T/inmunología , Linfocitos T/trasplante , Microambiente Tumoral/inmunología , Neoplasias Hematológicas/terapia , Neoplasias Hematológicas/inmunología , Antígenos de Neoplasias/inmunología , Receptores de Antígenos de Linfocitos T/inmunología
13.
Nanotheranostics ; 8(3): 380-400, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38751938

RESUMEN

Cancer is a multifactorial disease produced by mutations in the oncogenes and tumor suppressor genes, which result in uncontrolled cell proliferation and resistance to cell death. Cancer progresses due to the escape of altered cells from immune monitoring, which is facilitated by the tumor's mutual interaction with its microenvironment. Understanding the mechanisms involved in immune surveillance evasion and the significance of the tumor microenvironment might thus aid in developing improved therapies. Although in vivo models are commonly utilized, they could be better for time, cost, and ethical concerns. As a result, it is critical to replicate an in vivo model and recreate the cellular and tissue-level functionalities. A 3D cell culture, which gives a 3D architecture similar to that found in vivo, is an appropriate model. Furthermore, numerous cell types can be cocultured, establishing cellular interactions between TME and tumor cells. Moreover, microfluidics perfusion can provide precision flow rates, thus simulating tissue/organ function. Immunotherapy can be used with the perfused 3D cell culture technique to help develop successful therapeutics. Immunotherapy employing nano delivery can target the spot and silence the responsible genes, ensuring treatment effectiveness while minimizing adverse effects. This study focuses on the importance of 3D cell culture in understanding the pathophysiology of 3D tumors and TME, the function of TME in drug resistance, tumor progression, and the development of advanced anticancer therapies for high-throughput drug screening.


Asunto(s)
Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Inmunoterapia/métodos , Neoplasias/terapia , Microambiente Tumoral/efectos de los fármacos , Dispositivos Laboratorio en un Chip , Animales , Línea Celular Tumoral , Perfusión
14.
Molecules ; 29(9)2024 May 02.
Artículo en Inglés | MEDLINE | ID: mdl-38731601

RESUMEN

Alterations in cellular metabolism, such as dysregulation in glycolysis, lipid metabolism, and glutaminolysis in response to hypoxic and low-nutrient conditions within the tumor microenvironment, are well-recognized hallmarks of cancer. Therefore, understanding the interplay between aerobic glycolysis, lipid metabolism, and glutaminolysis is crucial for developing effective metabolism-based therapies for cancer, particularly in the context of colorectal cancer (CRC). In this regard, the present review explores the complex field of metabolic reprogramming in tumorigenesis and progression, providing insights into the current landscape of small molecule inhibitors targeting tumorigenic metabolic pathways and their implications for CRC treatment.


Asunto(s)
Antineoplásicos , Neoplasias Colorrectales , Humanos , Neoplasias Colorrectales/tratamiento farmacológico , Neoplasias Colorrectales/metabolismo , Neoplasias Colorrectales/patología , Antineoplásicos/uso terapéutico , Antineoplásicos/farmacología , Microambiente Tumoral/efectos de los fármacos , Animales , Glucólisis/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/farmacología , Bibliotecas de Moléculas Pequeñas/uso terapéutico , Metabolismo de los Lípidos/efectos de los fármacos , Redes y Vías Metabólicas/efectos de los fármacos
15.
BMC Endocr Disord ; 24(1): 68, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734621

RESUMEN

BACKGROUND: To date, although most thyroid carcinoma (THCA) achieves an excellent prognosis, some patients experience a rapid progression episode, even with differentiated THCA. Nodal metastasis is an unfavorable predictor. Exploring the underlying mechanism may bring a deep insight into THCA. METHODS: A total of 108 THCA from Chinese patients with next-generation sequencing (NGS) were recruited. It was used to explore the gene alteration spectrum of THCA and identify gene alterations related to nodal metastasis in papillary thyroid carcinoma (PTC). The Cancer Genome Atlas THCA cohort was further studied to elucidate the relationship between specific gene alterations and tumor microenvironment. A pathway enrichment analysis was used to explore the underlying mechanism. RESULTS: Gene alteration was frequent in THCA. BRAF, RET, POLE, ATM, and BRCA1 were the five most common altered genes. RET variation was positively related to nodal metastasis in PTC. RET variation is associated with immune cell infiltration levels, including CD8 naïve, CD4 T and CD8 T cells, etc. Moreover, Step 3 and Step 4 of the cancer immunity cycle (CIC) were activated, whereas Step 6 was suppressed in PTC with RET variation. A pathway enrichment analysis showed that RET variation was associated with several immune-related pathways. CONCLUSION: RET variation is positively related to nodal metastasis in Chinese PTC, and anti-tumor immune response may play a role in nodal metastasis triggered by RET variation.


Asunto(s)
Secuenciación de Nucleótidos de Alto Rendimiento , Metástasis Linfática , Proteínas Proto-Oncogénicas c-ret , Cáncer Papilar Tiroideo , Neoplasias de la Tiroides , Microambiente Tumoral , Humanos , Microambiente Tumoral/inmunología , Cáncer Papilar Tiroideo/genética , Cáncer Papilar Tiroideo/patología , Cáncer Papilar Tiroideo/inmunología , Proteínas Proto-Oncogénicas c-ret/genética , Femenino , Neoplasias de la Tiroides/genética , Neoplasias de la Tiroides/patología , Neoplasias de la Tiroides/inmunología , Masculino , Persona de Mediana Edad , Adulto , Pronóstico , Biomarcadores de Tumor/genética , Estudios de Seguimiento
16.
J Transl Med ; 22(1): 444, 2024 May 11.
Artículo en Inglés | MEDLINE | ID: mdl-38734658

RESUMEN

BACKGROUND: Characterization of shared cancer mechanisms have been proposed to improve therapy strategies and prognosis. Here, we aimed to identify shared cell-cell interactions (CCIs) within the tumor microenvironment across multiple solid cancers and assess their association with cancer mortality. METHODS: CCIs of each cancer were identified by NicheNet analysis of single-cell RNA sequencing data from breast, colon, liver, lung, and ovarian cancers. These CCIs were used to construct a shared multi-cellular tumor model (shared-MCTM) representing common CCIs across cancers. A gene signature was identified from the shared-MCTM and tested on the mRNA and protein level in two large independent cohorts: The Cancer Genome Atlas (TCGA, 9185 tumor samples and 727 controls across 22 cancers) and UK biobank (UKBB, 10,384 cancer patients and 5063 controls with proteomics data across 17 cancers). Cox proportional hazards models were used to evaluate the association of the signature with 10-year all-cause mortality, including sex-specific analysis. RESULTS: A shared-MCTM was derived from five individual cancers. A shared gene signature was extracted from this shared-MCTM and the most prominent regulatory cell type, matrix cancer-associated fibroblast (mCAF). The signature exhibited significant expression changes in multiple cancers compared to controls at both mRNA and protein levels in two independent cohorts. Importantly, it was significantly associated with mortality in cancer patients in both cohorts. The highest hazard ratios were observed for brain cancer in TCGA (HR [95%CI] = 6.90[4.64-10.25]) and ovarian cancer in UKBB (5.53[2.08-8.80]). Sex-specific analysis revealed distinct risks, with a higher mortality risk associated with the protein signature score in males (2.41[1.97-2.96]) compared to females (1.84[1.44-2.37]). CONCLUSION: We identified a gene signature from a comprehensive shared-MCTM representing common CCIs across different cancers and revealed the regulatory role of mCAF in the tumor microenvironment. The pathogenic relevance of the gene signature was supported by differential expression and association with mortality on both mRNA and protein levels in two independent cohorts.


Asunto(s)
Neoplasias , Humanos , Neoplasias/genética , Neoplasias/mortalidad , Femenino , Masculino , Regulación Neoplásica de la Expresión Génica , ARN Mensajero/genética , ARN Mensajero/metabolismo , Microambiente Tumoral/genética , Estudios de Cohortes , Transcriptoma/genética , Persona de Mediana Edad , Comunicación Celular
17.
Front Immunol ; 15: 1382931, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38736882

RESUMEN

Background: Neuroblastoma (NB) is characterized by both adrenergic (ADRN) and undifferentiated mesenchymal (MES) subsets. The ganglioside sialic acid-containing glycosphingolipid (GD2) is widely overexpressed on tumors of neuroectodermal origin promoting malignant phenotypes. MES cells are greatly enriched in post-therapy and relapsing tumors and are characterized by decreased expression of GD2. This event may cause failure of GD2-based immunotherapy. NK cells represent a key innate cell subset able to efficiently kill tumors. However, the tumor microenvironment (TME) that includes tumor cells and tumor-associated (TA) cells could inhibit their effector function. Methods: We studied eight NB primary cultures that, in comparison with commercial cell lines, more faithfully reflect the tumor cell characteristics. We studied four primary NB-MES cell cultures and two pairs of MES/ADRN (691 and 717) primary cultures, derived from the same patient. In particular, in the six human NB primary cultures, we assessed their phenotype, the expression of GD2, and the enzymes that control its expression, as well as their interactions with NK cells, using flow cytometry, RT-qPCR, and cytotoxicity assays. Results: We identified mature (CD105+/CD133-) and undifferentiated (CD133+/CD105-) NB subsets that express high levels of the MES transcripts WWTR1 and SIX4. In addition, undifferentiated MES cells display a strong resistance to NK-mediated killing. On the contrary, mature NB-MES cells display an intermediate resistance to NK-mediated killing and exhibit some immunomodulatory capacities on NK cells but do not inhibit their cytolytic activity. Notably, independent from their undifferentiated or mature phenotype, NB-MES cells express GD2 that can be further upregulated in undifferentiated NB-MES cells upon co-culture with NK cells, leading to the generation of mature mesenchymal GD2bright neuroblasts. Concerning 691 and 717, they show high levels of GD2 and resistance to NK cell-mediated killing that can be overcome by the administration of dinutuximab beta, the anti-GD2 monoclonal antibody applied in the clinic. Conclusions: NB is a heterogeneous tumor representing a further hurdle in NB immunotherapy. However, different from what was reported with NB commercial cells and independent of their MES/ADRN phenotype, the expression of GD2 and its displayed sensitivity to anti-GD2 mAb ADCC indicated the possible effectiveness of anti-GD2 immunotherapy.


Asunto(s)
Gangliósidos , Células Asesinas Naturales , Neuroblastoma , Escape del Tumor , Microambiente Tumoral , Humanos , Neuroblastoma/inmunología , Neuroblastoma/metabolismo , Células Asesinas Naturales/inmunología , Células Asesinas Naturales/metabolismo , Gangliósidos/inmunología , Gangliósidos/metabolismo , Microambiente Tumoral/inmunología , Línea Celular Tumoral , Citotoxicidad Inmunológica , Células Tumorales Cultivadas , Células Madre Mesenquimatosas/inmunología , Células Madre Mesenquimatosas/metabolismo
18.
Front Immunol ; 15: 1333923, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38736884

RESUMEN

Backgroud: Although recent studies have reported the regulation of the immune response in hepatocellular carcinoma (HCC) through DNA methylation, the comprehensive impact methylation modifications on tumor microenvironment characteristics and immunotherapy efficacy has not been fully elucidated. Methods: In this research, we conducted a comprehensive assessment of the patterns of DNA methylation regulators and the profiles of the tumor microenvironment (TME) in HCC, focusing on 21 specific DNA methylation regulators. We subsequently developed a unique scoring system, a DNA methylation score (DMscore), to assess the individual DNA methylation modifications among the three distinct methylation patterns for differentially expressed genes (DEGs). Results: Three distinct methylation modification patterns were identified with distinct TME infiltration characteristics. We demonstrated that the DMscore could predict patient subtype, TME infiltration, and patient prognosis. A low DMscore, characterized by an elevated tumor mutation burden (TMB), hepatitis B virus (HBV)/hepatitis C virus (HCV) infection, and immune activation, indicates an inflamed tumor microenvironment phenotype with a 5-year survival rate of 7.8%. Moreover, a low DMscore appeared to increase the efficacy of immunotherapy in the anti-CTLA-4/PD-1/PD-L1 cohort. Conclusions: In brief, this research has enhanced our understanding of the correlation between modifications in DNA methylation patterns and the profile of the tumor microenvironment in individuals diagnosed with HCC. The DMscore may serve as an alternative biomarker for survival and efficacy of immunotherapy in patients with HCC.


Asunto(s)
Biomarcadores de Tumor , Carcinoma Hepatocelular , Metilación de ADN , Regulación Neoplásica de la Expresión Génica , Neoplasias Hepáticas , Microambiente Tumoral , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/inmunología , Carcinoma Hepatocelular/patología , Humanos , Microambiente Tumoral/inmunología , Microambiente Tumoral/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/inmunología , Neoplasias Hepáticas/patología , Neoplasias Hepáticas/mortalidad , Biomarcadores de Tumor/genética , Pronóstico , Perfilación de la Expresión Génica
19.
Front Immunol ; 15: 1369892, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38707897

RESUMEN

Background: The transcription factor, SOX13 is part of the SOX family. SOX proteins are crucial in the progression of many cancers, and some correlate with carcinogenesis. Nonetheless, the biological and clinical implications of SOX13 in human breast cancer (BC) remain rarely known. Methods: We evaluated the survival and expression data of SOX13 in BC patients via the UNLCAL, GEPIA, TIMER, and Kaplan-Meier plotter databases. Immunohistochemistry (IHC) was used to verify clinical specimens. The gene alteration rates of SOX13 were acquired on the online web cBioportal. With the aid of the TCGA data, the association between SOX13 mRNA expression and copy number alterations (CNA) and methylation was determined. LinkedOmics was used to identify the genes that co-expressed with SOX13 and the regulators. Immune infiltration and tumor microenvironment evaluations were assessed by ImmuCellAI and TIMER2.0 databases. SOX13 correlated drug resistance analysis was performed using the GDSC2 database. Results: Higher SOX13 expression was discovered in BC tissues in comparison to normal tissues. Moreover, increased gene mutation and amplification of SOX13 were found in BC. Patients with increased SOX13 expression levels showed worse overall survival (OS). Cox analysis showed that SOX13 independently served as a prognostic indicator for poor survival in BC. Further, the expression of SOX13 was also confirmed to be correlated with tumor microenvironment and diverse infiltration of immune cells. In terms of drug sensitivity analysis, we found higher expression level of SOX13 predicts a high IC50 value for most of 198 drugs which predicts drug resistance. Conclusion: The present findings demonstrated that high expression of SOX13 negatively relates to prognosis and SOX13 plays an important role in cancer immunity. Therefore, SOX13 may potentially be adopted as a biomarker for predicting BC prognosis and infiltration of immune cells.


Asunto(s)
Biomarcadores de Tumor , Neoplasias de la Mama , Regulación Neoplásica de la Expresión Génica , Microambiente Tumoral , Humanos , Neoplasias de la Mama/inmunología , Neoplasias de la Mama/mortalidad , Neoplasias de la Mama/genética , Neoplasias de la Mama/metabolismo , Femenino , Biomarcadores de Tumor/genética , Pronóstico , Microambiente Tumoral/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/metabolismo , Resistencia a Antineoplásicos/genética , Estimación de Kaplan-Meier
20.
Int J Nanomedicine ; 19: 3919-3942, 2024.
Artículo en Inglés | MEDLINE | ID: mdl-38708176

RESUMEN

Typical physiological characteristics of tumors, such as weak acidity, low oxygen content, and upregulation of certain enzymes in the tumor microenvironment (TME), provide survival advantages when exposed to targeted attacks by drugs and responsive nanomedicines. Consequently, cancer treatment has significantly progressed in recent years. However, the evolution and adaptation of tumor characteristics still pose many challenges for current treatment methods. Therefore, efficient and precise cancer treatments require an understanding of the heterogeneity degree of various factors in cancer cells during tumor evolution to exploit the typical TME characteristics and manage the mutation process. The highly heterogeneous tumor and infiltrating stromal cells, immune cells, and extracellular components collectively form a unique TME, which plays a crucial role in tumor malignancy, including proliferation, invasion, metastasis, and immune escape. Therefore, the development of new treatment methods that can adapt to the evolutionary characteristics of tumors has become an intense focus in current cancer treatment research. This paper explores the latest understanding of cancer evolution, focusing on how tumors use new antigens to shape their "new faces"; how immune system cells, such as cytotoxic T cells, regulatory T cells, macrophages, and natural killer cells, help tumors become "invisible", that is, immune escape; whether the diverse cancer-associated fibroblasts provide support and coordination for tumors; and whether it is possible to attack tumors in reverse. This paper discusses the limitations of targeted therapy driven by tumor evolution factors and explores future strategies and the potential of intelligent nanomedicines, including the systematic coordination of tumor evolution factors and adaptive methods, to meet this therapeutic challenge.


Asunto(s)
Inmunoterapia , Neoplasias , Microambiente Tumoral , Humanos , Microambiente Tumoral/efectos de los fármacos , Inmunoterapia/métodos , Neoplasias/tratamiento farmacológico , Neoplasias/terapia , Neoplasias/inmunología , Nanomedicina/métodos , Animales , Nanopartículas/química , Antineoplásicos/química , Antineoplásicos/farmacología
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