RESUMO
Radiotherapy has unique immunostimulatory and immunosuppressive effects. Although high-dose radiotherapy has been found to have systemic antitumor effects, clinically significant abscopal effects were uncommon on the basis of irradiating single lesion. Low-dose radiation therapy (LDRT) emerges as a novel approach to enhance the antitumor immune response due to its role as a leverage to reshape the tumor immune microenvironment (TIME). In this article, from bench to bedside, we reviewed the possible immunomodulatory role of LDRT on TIME and systemic tumor immune environment, and outlined preclinical evidence and clinical application. We also discussed the current challenges when LDRT is used as a combination therapy, including the optimal dose, fraction, frequency, and combination of drugs. The advantage of low toxicity makes LDRT potential to be applied in multiple lesions to amplify antitumor immune response in polymetastatic disease, and its intersection with other disciplines might also make it a direction for radiotherapy-combined modalities.
Assuntos
Neoplasias , Humanos , Neoplasias/radioterapia , Previsões , Imunidade , Terapia Combinada , Imunomodulação , Imunoterapia , Microambiente TumoralRESUMO
BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy with high probability of recurrence and distant metastasis. Liver metastasis is the predominant metastatic mode developed in most pancreatic cancer cases, which seriously affects the overall survival rate of patients. Abnormally activated endoplasmic reticulum stress and lipid metabolism reprogramming are closely related to tumor growth and metastasis. This study aims to construct a prognostic model based on endoplasmic reticulum stress and lipid metabolism for pancreatic cancer, and further explore its correlation with tumor immunity and the possibility of immunotherapy. METHODS: Transcriptomic and clinical data are acquired from TCGA, ICGC, and GEO databases. Potential prognostic genes were screened by consistent clustering and WGCNA methods, and the whole cohort was randomly divided into training and testing groups. The prognostic model was constructed by machine learning method in the training cohort and verified in the test, TCGA and ICGC cohorts. The clinical application of this model and its relationship with tumor immunity were analyzed, and the relationship between endoplasmic reticulum stress and intercellular communication was further explored. RESULTS: A total of 92 characteristic genes related to endoplasmic reticulum stress, lipid metabolism and liver metastasis were identified in pancreatic cancer. We established and validated a prognostic model for pancreatic cancer with 7 signatures, including ADH1C, APOE, RAP1GAP, NPC1L1, P4HB, SOD2, and TNFSF10. This model is considered to be an independent prognosticator and is a more accurate predictor of overall survival than age, gender, and stage. TIDE score was increased in high-risk group, while the infiltration levels of CD8+ T cells and M1 macrophages were decreased. The number and intensity of intercellular communication were increased in the high ER stress group. CONCLUSIONS: We constructed and validated a novel prognostic model for pancreatic cancer, which can also be used as an instrumental variable to predict the prognosis and immune microenvironment. In addition, this study revealed the effect of ER stress on cell-cell communication in the tumor microenvironment.
Assuntos
Estresse do Retículo Endoplasmático , Regulação Neoplásica da Expressão Gênica , Metabolismo dos Lipídeos , Neoplasias Hepáticas , Neoplasias Pancreáticas , Análise de Célula Única , Transcriptoma , Humanos , Estresse do Retículo Endoplasmático/genética , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/patologia , Metabolismo dos Lipídeos/genética , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/secundário , Neoplasias Hepáticas/patologia , Transcriptoma/genética , Prognóstico , Masculino , Feminino , Pessoa de Meia-Idade , Perfilação da Expressão Gênica , Reprodutibilidade dos Testes , Estudos de CoortesRESUMO
The close link between immune and pathogenesis of venous thromboembolism (VTE) has been recognized, but not fully elucidated. The current study was designed to identify immune microenvironment related signature and subtypes using explainable machine learning in VTE. We first observed an alteration of immune microenvironment in VTE patients and identified eight key immune cells involved in VTE. Then PTPN6, ITGB2, CR2, FPR2, MMP9 and ISG15 were determined as key immune microenvironment-related genes, which could divide VTE patients into two subtypes with different immune and metabolic characteristics. Also, we found that prunetin and torin-2 may be most promising to treat VTE patients in Cluster 1 and 2, respectively. By comparing six machine learning models in both training and external validation sets, XGboost was identified as the best one to predict the risk of VTE, followed by the interpretation of each immune microenvironment-related gene contributing to the model. Moreover, CR2 and FPR2 had high accuracy in distinguishing VTE and control, which may act as diagnostic biomarkers of VTE, and their expressions were validated by qPCR. Collectively, immune microenvironment related PTPN6, ITGB2, CR2, FPR2, MMP9 and ISG15 are key genes involved in the pathogenesis of VTE. The VTE risk prediction model and immune microenvironment subtypes based on those genes might benefit prevention, diagnosis, and the individualized treatment strategy in clinical practice of VTE.
Assuntos
Tromboembolia Venosa , Humanos , Tromboembolia Venosa/imunologia , Masculino , Feminino , Pessoa de Meia-Idade , Biomarcadores/metabolismo , Aprendizado de Máquina , Microambiente Celular/imunologiaRESUMO
BACKGROUND: A water-soluble ingredient of mature leaves of the tropical mahogany 'Neem' (Azadirachta indica), was identified as glycoprotein, thus being named as 'Neem Leaf Glycoprotein' (NLGP). This non-toxic leaf-component regressed cancerous murine tumors (melanoma, carcinoma, sarcoma) recurrently in different experimental circumstances by boosting prime antitumor immune attributes. Such antitumor immunomodulation, aid cytotoxic T cell (Tc)-based annihilation of tumor cells. This study focused on identifying and characterizing the signaling gateway that initiate this systemic immunomodulation. In search of this gateway, antigen-presenting cells (APCs) were explored, which activate and induce the cytotoxic thrust in Tc cells. METHODS: Six glycoprotein-binding C-type lectins found on APCs, namely, MBR, Dectin-1, Dectin-2, DC-SIGN, DEC205 and DNGR-1 were screened on bone marrow-derived dendritic cells from C57BL/6 J mice. Fluorescence microscopy, RT-PCR, flow cytometry and ELISA revealed Dectin-1 as the NLGP-binding receptor, followed by verifications through RNAi. Following detection of ß-Glucans in NLGP, their interactions with Dectin-1 were explored in silico. Roles of second messengers and transcription factors in the downstream signal were studied by co-immunoprecipitation, western blotting, and chromatin-immunoprecipitation. Intracellularization of FITC-coupled NLGP was observed by processing confocal micrographs of DCs. RESULTS: Considering extents of hindrance in NLGP-driven transcription rates of the cytokines IL-10 and IL-12p35 by receptor-neutralization, Dectin-1 receptors on dendritic cells were found to bind NLGP through the ligand's peripheral ß-Glucan chains. The resulting signal phosphorylates PKCδ, forming a trimolecular complex of CARD9, Bcl10 and MALT1, which in turn activates the canonical NFκB-pathway of transcription-regulation. Consequently, the NFκB-heterodimer p65:p50 enhances Il12a transcription and the p50:p50 homodimer represses Il10 transcription, bringing about a cytokine-based systemic-bias towards type-1 immune environment. Further, NLGP gets engulfed within dendritic cells, possibly through endocytic activities of Dectin-1. CONCLUSION: NLGP's binding to Dectin-1 receptors on murine dendritic cells, followed by the intracellular signal, lead to NFκB-mediated contrasting regulation of cytokine-transcriptions, initiating a pro-inflammatory immunopolarization, which amplifies further by the responding immune cells including Tc cells, alongside their enhanced cytotoxicity. These insights into the initiation of mammalian systemic immunomodulation by NLGP at cellular and molecular levels, may help uncovering its mode of action as a novel immunomodulator against human cancers, following clinical trials.
Assuntos
Azadirachta , Proteínas Adaptadoras de Sinalização CARD , Células Dendríticas , Lectinas Tipo C , Camundongos Endogâmicos C57BL , NF-kappa B , Folhas de Planta , Transdução de Sinais , Animais , Lectinas Tipo C/metabolismo , Lectinas Tipo C/genética , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Azadirachta/química , Camundongos , Proteínas Adaptadoras de Sinalização CARD/metabolismo , NF-kappa B/metabolismo , Ligação ProteicaRESUMO
Activins and inhibins are unique members of the transforming growth factor-ß (TGFß) family of growth factors, with the ability to exert autocrine, endocrine, and paracrine effects in a wide range of complex physiologic and pathologic processes. Although first isolated within the pituitary, emerging evidence suggests broader influence beyond reproductive development and function. Known roles of activin and inhibin in angiogenesis and immunity along with correlations between gene expression and cancer prognosis suggest potential roles in tumorigenesis. Here, we present a review of the current understanding of the biological role of activins and inhibins as it relates to ovarian cancers, summarizing the underlying signaling mechanisms and physiologic influence, followed by detailing their roles in cancer progression, diagnosis, and treatment.
Assuntos
Inibinas , Neoplasias Ovarianas , Humanos , Feminino , Inibinas/genética , Inibinas/metabolismo , Ativinas/genética , Ativinas/metabolismo , Neoplasias Ovarianas/genética , Transdução de Sinais , Sistema Endócrino/metabolismoRESUMO
Amino acids are essential for the survival of all living organisms and living cells. Amino acid transporters mediate the transport and absorption of amino acids, and the dysfunction of these proteins can induce human diseases. Cationic amino acid transporters (CAT family, SLC7A1-4, and SLC7A14) are considered to be a group of transmembrane transporters, of which SLC7A1-3 are essential for arginine transport in mammals. Numerous studies have shown that CAT family-mediated arginine transport is involved in signal crosstalk between malignant tumor cells and immune cells, especially T cells. The modulation of extracellular arginine concentration has entered a number of clinical trials and achieved certain therapeutic effects. Here, we review the role of CAT family on tumor cells and immune infiltrating cells in malignant tumors and explore the therapeutic strategies to interfere with extracellular arginine concentration, to elaborate its application prospects. CAT family members may be used as biomarkers for certain cancer entities and might be included in new ideas for immunotherapy of malignant tumors.
Assuntos
Sistemas de Transporte de Aminoácidos Básicos , Neoplasias , Animais , Humanos , Sistemas de Transporte de Aminoácidos Básicos/genética , Sistemas de Transporte de Aminoácidos Básicos/metabolismo , Arginina/metabolismo , Aminoácidos/metabolismo , Transportador 1 de Aminoácidos Catiônicos/metabolismo , Transporte Biológico , Transportador 2 de Aminoácidos Catiônicos/metabolismo , Mamíferos/metabolismo , Microambiente TumoralRESUMO
Increasing evidences have demonstrated that pyroptosis exerts key roles in the occurrence, development of chronic obstructive pulmonary disease. However, the mechanisms of pyroptosis in COPD remain largely unknown. In our research, Statistics were performed using R software and related packages in this study. Series matrix files of small airway epithelium samples were downloaded from the GEO database. Differential expression analysis with FDR < 0.05 was performed to identify COPD-associated pyroptosis-related genes. 8 up-regulated genes (CASP4, CASP5, CHMP7, GZMB, IL1B, AIM2, CASP6, GSDMC) and 1 down-regulated genes (PLCG1) was identified as COPD-associated pyroptosis-related genes. Twenty-six COPD key genes was identified by WGCNA analysis. PPI analysis and gene correlation analysis showed their relationship clearly. KEGG and GO analysis have revealed the main pyroptosis-related mechanism of COPD. The expression of 9 COPD-associated pyroptosis-related genes in different grades was also depicted. The immune environment of COPD was also explored. Furthermore, the relationship of pyroptosis-related genes and the expression of immune cells was also be shown in the end. In the end, we concluded that pyroptosis influences the development of COPD. This study may provide new insight into the novel therapeutic targets for COPD clinical treatment.
Assuntos
Doença Pulmonar Obstrutiva Crônica , Piroptose , Humanos , Piroptose/genética , Doença Pulmonar Obstrutiva Crônica/genética , Caspases , Bases de Dados Factuais , Epitélio , Biomarcadores Tumorais , Proteínas Citotóxicas Formadoras de Poros , Complexos Endossomais de Distribuição Requeridos para TransporteRESUMO
BACKGROUND: PI3K pathway is the most frequently mutated pathway in head and neck squamous cell carcinoma (HNSC), which plays a crucial role in tumorigenesis and progression. In the present study, we aimed to investigate the role of PI3K pathway mutation in clinical prognosis prediction and the relationship with immune microenvironment and response rate to immunotherapy. METHODS: We collected 129 samples with immunotherapy information from MSKCC-2019 cohort as well as 501 and 40 samples from TCGA-HNSC and MD-Anderson non-immunotherapy cohorts, respectively. Somatic mutation data was utilized to characterize the mutational status of the PI3K pathway. Subsequently, we further analyzed the differences in prognosis, immunotherapy response, genomic alterations, functional characteristics, and immune microenvironment between the mutation and wild groups. RESULTS: The Kaplan-Meier survival curves displayed that PI3K pathway mutation predicted observably prolonged overall survival (OS) in the immunotherapy cohort MSKCC-2019 (p = 0.012) but did not reach statistical significance in the non-immunotherapy cohorts TCGA-HNSC (p = 0.68) and MD-Anderson (p = 0.68). After incorporating several clinicopathologic features such as age, gender, and tumor mutation burden (TMB), the results of multivariate Cox regression analysis also demonstrated that the PI3K pathway mutation could indicate better immunotherapy outcomes in HNSC patients with a hazard ratio (HR) of 0.533 (95% CI: 0.313-0.910; p = 0.021) in the immunotherapy cohort MSKCC-2019, compared with 0.888 (95% CI: 0.636-1.241; p = 0.487) and 1.939 (95% CI: 0.483-7.781; p = 0.351) in the non-immunotherapy cohorts TCGA-HNSC and MD-Anderson. In addition, the results of the subclass mapping (SubMap) and the tumor immune dysfunction and exclusion (TIDE) also consistently suggested that patients in the mutation group are more likely to benefit from immunotherapy. And further studies showed that the mutation group owned significantly higher TMB, activated immune-related pathways, richer abundance of immune cells, and higher expression levels of immunomodulators. To improve the prognosis of the wild group, we identified five relatively sensitive potential drugs for the wild group, including "BMS-536924," "linsitinib," "NVP-TAE684," "PLX-4720," and "clonazepam." CONCLUSIONS: The PI3K pathway mutation status could be considered as a potential biomarker to predict better immunotherapeutic efficacy and clinical outcomes after immunotherapy in HNSC patients.
Assuntos
Neoplasias de Cabeça e Pescoço , Fosfatidilinositol 3-Quinases , Humanos , Fosfatidilinositol 3-Quinases/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Carcinoma de Células Escamosas de Cabeça e Pescoço/terapia , Carcinogênese , Imunoterapia , Neoplasias de Cabeça e Pescoço/genética , Neoplasias de Cabeça e Pescoço/terapia , Microambiente TumoralRESUMO
There is increasing evidence in a range of cancer types that the microbiome plays a direct role in modulating the anti-cancer immune response both at the gut level and systemically. Differences in the gut microbiota have been shown to correlate with differences in immunotherapy responses in a range of non-gastrointestinal tract cancers. DNA mismatch repair-deficient (dMMR) colorectal cancer (CRC) is radically different to DNA mismatch repair-proficient (pMMR) CRC in clinical phenotype and in its very good responses to immunotherapy. While this has usually been thought to be due to the high mutational burden in dMMR CRC, the gut microbiome is radically different in dMMR and pMMR CRC in terms of both composition and diversity. It is probable that differences in the gut microbiota contribute to the varied responses to immunotherapy in dMMR versus pMMR CRC. Targeting the microbiome offers a way to boost the response and increase the selection of patients who might benefit from this therapy. This paper reviews the available literature on the role of the microbiome in the response to immunotherapy in dMMR and pMMR CRC, explores the potential causal relationship and discusses future directions for study in this exciting and rapidly changing field.
Assuntos
Neoplasias Colorretais , Microbioma Gastrointestinal , Humanos , Microbioma Gastrointestinal/genética , Neoplasias Colorretais/terapia , Neoplasias Colorretais/tratamento farmacológico , Imunoterapia , Repetições de Microssatélites , Reparo de Erro de Pareamento de DNA , Instabilidade de MicrossatélitesRESUMO
Immune environment plays an important role in the management of liver cancer. The current study aimed to explore the change of NK and NKT cells, IL-17A, CD4+ T and CD8+ T cells in refractory liver metastases patients before and after CalliSpheres® microspheres transarterial chemoembolization (CSM-TACE). Peripheral blood (PB) samples from 35 refractory liver metastases patients were collected before CSM-TACE (baseline), 2 days (D2) and 5 days (D5) after CSM-TACE. Then, NK and NKT cells, IL-17A, CD4+ T and CD8+ T cells from PB samples were detected. All enrolled patients successfully completed CSM-TACE procedure and achieved disease control rate of 100% after 1 month. NKT cells were increased from baseline to D2 and D5 [median (range): 5.88% (1.53%-12.05%) vs. 9.54% (5.19%-15.71%) vs. 7.12% (2.77%-13.29%)], NK cells were also enhanced from baseline to D2 and D5 [median (range): 14.35% (5.85%-20.52%) vs. 20.36% (15.88%-27.30%) vs. 30.82% (22.18%-37.72%)], while IL-17A was declined from baseline to D2 and D5 [median (range): 22.11 (9.46-39.18) pg/ml vs. 12.41 (3.24-26.84) pg/ml vs. 6.55 (1.11-20.98) pg/ml]. Furthermore, IL-17A was negatively correlated with the NK and NKT cells at baseline, D2 and D5 (all p < .05), respectively. Additionally, CD4+ T cells and CD4+ T/CD8+ T ratio were increased while CD8+ T cells were declined from baseline to D2 and D5 (all p < .05). NK cells, NKT cells, and CD4+ T cells are increased but IL-17A and CD8+ T cells are declined after CSM-TACE in refractory liver metastases.
Assuntos
Carcinoma Hepatocelular , Quimioembolização Terapêutica , Neoplasias Hepáticas , Humanos , Neoplasias Hepáticas/terapia , Neoplasias Hepáticas/patologia , Carcinoma Hepatocelular/patologia , Linfócitos T CD8-Positivos , Interleucina-17 , Microesferas , Quimioembolização Terapêutica/métodos , Linfócitos T CD4-Positivos/patologiaRESUMO
BACKGROUND: Although the tumour immune microenvironment is known to significantly influence immunotherapy outcomes, its association with changes in gene expression patterns in hepatocellular carcinoma (HCC) during immunotherapy and its effect on prognosis have not been clarified. METHODS: A total of 365 HCC samples from The Cancer Genome Atlas liver hepatocellular carcinoma (TCGA-LIHC) dataset were stratified into training datasets and verification datasets. In the training datasets, immune-related genes were analysed through univariate Cox regression analyses and least absolute shrinkage and selection operator (LASSO)-Cox analyses to build a prognostic model. The TCGA-LIHC, GSE14520, and Imvigor210 cohorts were subjected to time-dependent receiver operating characteristic (ROC) and Kaplan-Meier survival curve analyses to verify the reliability of the developed model. Finally, single-sample gene set enrichment analysis (ssGSEA) was used to study the underlying molecular mechanisms. RESULTS: Five immune-related genes (LDHA, PPAT, BFSP1, NR0B1, and PFKFB4) were identified and used to establish the prognostic model for patient response to HCC treatment. ROC curve analysis of the TCGA (training and validation sets) and GSE14520 cohorts confirmed the predictive ability of the five-gene-based model (AUC > 0.6). In addition, ROC and Kaplan-Meier analyses indicated that the model could stratify patients into a low-risk and a high-risk group, wherein the high-risk group exhibited worse prognosis and was less sensitive to immunotherapy than the low-risk group. Functional enrichment analysis predicted potential associations of the five genes with several metabolic processes and oncological signatures. CONCLUSIONS: We established a novel five-gene-based prognostic model based on the tumour immune microenvironment that can predict immunotherapy efficacy in HCC patients.
Assuntos
Carcinoma Hepatocelular , Neoplasias Hepáticas , Biomarcadores Tumorais/genética , Carcinoma Hepatocelular/genética , Carcinoma Hepatocelular/terapia , Perfilação da Expressão Gênica , Regulação Neoplásica da Expressão Gênica , Humanos , Imunoterapia , Neoplasias Hepáticas/genética , Neoplasias Hepáticas/terapia , Reprodutibilidade dos Testes , Microambiente Tumoral/genéticaRESUMO
BACKGROUND: Ubiquitin-conjugating enzyme E2W (UBE2W) is a protein-coding gene that has an important role in ubiquitination and may be vital in the repair of DNA damage. However, studies on the prognostic value of UBE2W and its correlation with tumor-infiltrating immune cells in multiple cancers have not been addressed. METHODS: We investigated UBE2W expression in the Oncomine database, the Tumor Immune Estimation Resource (TIMER), TNMplot database. Then, the clinical prognostic value of UBE2W was analyzed via online public databases. Meanwhile, we explored the correlation between UBE2W and DNA repair associate genes expression and DNA methyltransferase expression by TIMER and Gene Expression Profiling Interactive Analysis (GEPIA). By using the same method, the correlation between UBE2W and tumor-infiltrating immune cells was explored. Genomic Profiles of UBE2W in breast cancer (BRCA) were accessed in cBioPortal (v3.5.0). Functional proteins associated network was analyzed by STRING database (v11.0). RESULTS: UBE2W was abnormally expressed and significantly correlated with mismatch repair (MMR) gene mutation levels, DNA methyltransferase, and BRCA1/2 expression in breast cancer. High expression of UBE2W may promote the tumor immunosuppression and metastasis, induce endocrine therapy resistance and deteriorate outcomes of patients with breast cancer. These findings suggest that UBE2W could be a potential biomarker of prognosis and tumor-infiltrating immune cells. Besides, RBX1 may be a new E3 that was regulated by UBE2W. CONCLUSIONS: Ubiquitin E2 UBE2W is a potential prognostic biomarker and is correlated with immune infiltration in BRCA.
Assuntos
Neoplasias da Mama/imunologia , Neoplasias da Mama/metabolismo , Reparo de Erro de Pareamento de DNA/genética , Linfócitos do Interstício Tumoral , Enzimas de Conjugação de Ubiquitina/metabolismo , Neoplasias da Mama/mortalidade , Bases de Dados Factuais , Feminino , Expressão Gênica , Perfilação da Expressão Gênica , Genes BRCA1 , Genes BRCA2 , Humanos , Metiltransferases/metabolismo , Mutação , Neoplasias/metabolismo , Prognóstico , Microambiente Tumoral/imunologia , Enzimas de Conjugação de Ubiquitina/genética , UbiquitinaçãoRESUMO
As the core element of material and energy metabolism pathways, the biological functions and prognostic significance of ATP metabolism in diffuse gliomas have so far remained unclear. Based on comprehensive analysis of ATP metabolism-related gene expression profiles, we constructed an ATP metabolism-related risk signature to determine the role of ATP metabolism. We found that this ATP metabolism-related gene expression profile could divide patients into 2 robust groups with distinct clinical characteristics and prognosis. Patients in the high-risk group tended to be predicted as malignant entities, indicating that the activation of ATP metabolism may promote the malignant progress of diffuse gliomas. Cox regression and Kaplan-Meier analyses suggested that this risk signature was an independent predictor for prognosis. Furthermore, we constructed an individualized prognosis prediction model through nomogram and time-dependent receiver operating characteristic (ROC) curve analyses. Functional analysis suggested that, in addition to material and energy metabolism, ATP metabolism also played an essential role in the regulation of the tumor immune microenvironment. In brief, the ATP metabolism-related signature was tightly associated with regulation of the tumor immune microenvironment and could serve as an independent prognostic biomarker in diffuse gliomas.
Assuntos
Trifosfato de Adenosina/metabolismo , Biomarcadores Tumorais , Glioma/etiologia , Glioma/metabolismo , Metaboloma , Microambiente Tumoral/imunologia , Adulto , Biologia Computacional/métodos , Metilação de DNA , Regulação Neoplásica da Expressão Gênica , Glioma/mortalidade , Glioma/patologia , Humanos , Metabolômica/métodos , Pessoa de Meia-Idade , Anotação de Sequência Molecular , Gradação de Tumores , Prognóstico , Regiões Promotoras Genéticas , Curva ROC , Microambiente Tumoral/genéticaRESUMO
Aim: A gene set based systematic analysis strategy is used to investigate prostate tumors and its subclusters with focuses on similarities and differences of biological functions. Results: Dysregulation of methylation status, as well as RAS/RAF/ERK and PI3K-ATK signaling pathways, were found to be the most dramatic changes during prostate cancer tumorigenesis. Besides, neural and inflammation microenvironment is also significantly divergent between tumor and adjacent tissues. Insights of subclasses within prostate tumor cohorts revealed four different clusters with distinct gene expression patterns. We found that samples are mainly clustered by immune environments and proliferation traits. Conclusion: The findings of this article may help to advance the progress of identifying better diagnosis biomarkers and therapeutic targets.
Assuntos
Biomarcadores Tumorais/genética , Neoplasias da Próstata/classificação , Neoplasias da Próstata/genética , Tirosina Quinase da Agamaglobulinemia/genética , Biologia Computacional/métodos , MAP Quinases Reguladas por Sinal Extracelular/genética , Perfilação da Expressão Gênica , Humanos , Masculino , Gradação de Tumores , PTEN Fosfo-Hidrolase/genética , Fosfatidilinositol 3-Quinases/genética , Neoplasias da Próstata/enzimologia , Neoplasias da Próstata/patologia , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas c-akt/genética , Proteínas Proto-Oncogênicas c-raf/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Análise de Sequência de RNA/métodos , Transdução de Sinais , Taxa de SobrevidaRESUMO
The accumulation of mutated somatic cells due to the incompetency of body's immune system may lead to tumor onset. Therefore, enhancing the ability of the system to eliminate such cells should be the core of tumor therapy. The intrinsic antitumor immunity is triggered by tumor-specific antigens (TSA) or TSA-sensitized dendritic cells (DC). Once initiated, specific anti-tumor antibodies are produced and tumor-specific killer immune cells, including cytotoxic T lymphocytes (CTL), NK cells, and macrophages, are raised or induced. Several strategies may enhance antitumor action of immune system, such as supplying tumor-targeted antibody, activating T cells, enhancing the activity and tumor recognition of NK cells, promoting tumor-targeted phagocytosis of macrophages, and eliminating the immunosuppressive myeloid-derived suppressor cells (MDSCs) and Treg cells. Apart from the immune system, the removal of tumor burden still needs to be assisted by drugs, surgery or radiation. And the body's internal environment and tumor microenvironment should be improved to recover immune cell function and prevent tumor growth. Multiple microenvironment modulatory therapies may be applied, including addressing hypoxia and oxidative stress, correcting metabolic disorders, and controlling chronic inflammation. Finally, to cure tumor and prevent tumor recurrence, repairing or supporting therapy that consist of tissue repair and nutritional supplement should be applied properly.
Assuntos
Imunoterapia , Neoplasias/terapia , Anticorpos Antineoplásicos/uso terapêutico , Células Dendríticas/citologia , Células Dendríticas/imunologia , Células Dendríticas/metabolismo , Humanos , Sistema Imunitário/citologia , Sistema Imunitário/metabolismo , Células Matadoras Naturais/imunologia , Neoplasias/metabolismo , Neoplasias/patologia , Estresse Oxidativo , Linfócitos T Citotóxicos/imunologia , Microambiente TumoralRESUMO
BACKGROUND: Programmed cell death 1 (PD-1) functions as an immune checkpoint in the process of anti-tumor immune response. The PD-1 blockade is now becoming a fundamental part in cancer immunotherapy. So it's essential to elicit the PD-1 related immune process in different types of cancer. METHODS: The Cancer Genome Atlas was used to collect the RNA-seq data of 33 cancer types. The microenvironment cell populations-counter was used to analyze the immune cell infiltrates. KEGG and GO analysis were performed to investigate PD-1 associated biological process. Kaplan-Meier survival curves and Cox's proportional hazards model were performed for prognostic value analysis. RESULTS: We demonstrated that PD-1 expression varied in different cancer types. The uveal melanoma had a low PD-1 expression and poor infiltrated with immune cells. But it showed the strong correlation of PD-1 with the most types of immune cells. The PD-1 demonstrated a robust relationship with other immunomodulators and showed its involvement in critical functions correlated with anti-tumor immune pathways. Survival analysis indicated the PD-1 expression suggested different prognosis in different cancer types. CONCLUSIONS: Our investigations promote a better understanding of the PD-1 blockade and provide PD-1 related personized combined immunotherapy for different types of cancer patients.
RESUMO
An emerging picture in cancer biology is that, paradoxically, chemotherapy can actively induce changes that favor cancer progression. These pro-cancer changes can be either inside (intrinsic) or outside (extrinsic) the cancer cells. In this review, we will discuss the extrinsic pro-cancer effect of chemotherapy; that is, the effect of chemotherapy on the non-cancer host cells to promote cancer progression. We will focus on metastasis, and will first discuss recent data from mouse models of breast cancer. Despite reducing the size of primary tumors, chemotherapy changes the tumor microenvironment, resulting in an increased escape of cancer cells into the blood stream. Furthermore, chemotherapry changes the tissue microenvironment at the distant sites, making it more hospitable to cancer cells upon their arrival. We will then discuss the idea and evidence that these devastating pro-metastatic effects of chemotherapy can be explained in the context of adaptive-response. At the end, we will discuss the potential relevance of these mouse data to human breast cancer and their implication on chemotherapy in the clinic.
Assuntos
Antineoplásicos/uso terapêutico , Neoplasias da Mama/tratamento farmacológico , Metástase Neoplásica/tratamento farmacológico , Animais , Antineoplásicos/efeitos adversos , Mama/efeitos dos fármacos , Mama/patologia , Neoplasias da Mama/patologia , Movimento Celular/efeitos dos fármacos , Modelos Animais de Doenças , Progressão da Doença , Feminino , Humanos , Metástase Neoplásica/patologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
Targeting mutations and amplifications in the EGFR has been successful precision therapy for cancers of the lung, oral cavity and gastrointestinal track. However, a systemic immune reaction manifested by dose-limiting inflammation in the skin and gut has been a consistent adverse effect. To address the possibility that intra-tumoral immune changes contribute to the anti-cancer activity of EGFR inhibition, squamous cancers were produced by syngeneic orthografts of either EGFR null or wildtype mouse primary keratinocytes transduced with an oncogenic H-ras retrovirus. Flow cytometric, RNA and Bioplex immunoassay analyses of the tumor immune milieu were performed. Cancers forming from keratinocytes genetically depleted of EGFR were smaller than wildtype cancers and had fewer infiltrating FoxP3 Treg cells, lower Foxp3 RNA and a lower percentage of CD4 PD1 positive cells indicating a tumor cell autonomous regulation of its microenvironment. Hosts bearing wildtype cancers treated with gefitinib for 1 week showed a trend for smaller tumors. In this short term pharmacological model, there was also a trend to reduced FoxP3 cells and FoxP3 RNA in the tumors of treated mice as well as a substantial increase in the ratio of IL-1A/IL-1RA transcripts. These results suggest that relatively brief systemic inhibition of EGFR signaling alters the immune environment of the targeted cancer. Together these data imply that an EGFR dependent Treg function supports the growth of squamous cancers and is a target for the therapeutic activity of EGFR inhibition.
Assuntos
Carcinoma de Células Escamosas/enzimologia , Carcinoma de Células Escamosas/imunologia , Receptores ErbB/antagonistas & inibidores , Neoplasias Cutâneas/enzimologia , Neoplasias Cutâneas/imunologia , Animais , Carcinoma de Células Escamosas/tratamento farmacológico , Carcinoma de Células Escamosas/genética , Receptores ErbB/genética , Receptores ErbB/imunologia , Gefitinibe , Imunocompetência , Queratinócitos/efeitos dos fármacos , Queratinócitos/enzimologia , Queratinócitos/imunologia , Camundongos , Inibidores de Proteínas Quinases/farmacologia , Quinazolinas/farmacologia , Neoplasias Cutâneas/tratamento farmacológico , Neoplasias Cutâneas/genéticaRESUMO
With the current epidemic of obesity, a large number of patients diagnosed with cancer are overweight or obese. Importantly, this excess body weight is associated with tumor progression and poor prognosis. The mechanisms for this worse outcome, however, remain poorly understood. We review here the epidemiological evidence for the association between obesity and cancer, and discuss potential mechanisms focusing on angiogenesis and inflammation. In particular, we will discuss how the dysfunctional angiogenesis and inflammation occurring in adipose tissue in obesity may promote tumor progression, resistance to chemotherapy, and targeted therapies such as anti-angiogenic and immune therapies. Better understanding of how obesity fuels tumor progression and therapy resistance is essential to improve the current standard of care and the clinical outcome of cancer patients. To this end, we will discuss how an anti-diabetic drug such as metformin can overcome these adverse effects of obesity on the progression and treatment resistance of tumors.
Assuntos
Resistencia a Medicamentos Antineoplásicos/efeitos dos fármacos , Metformina/uso terapêutico , Neoplasias , Neovascularização Patológica , Obesidade , Animais , Humanos , Inflamação/tratamento farmacológico , Inflamação/metabolismo , Inflamação/patologia , Neoplasias/tratamento farmacológico , Neoplasias/metabolismo , Neoplasias/patologia , Neovascularização Patológica/tratamento farmacológico , Neovascularização Patológica/metabolismo , Neovascularização Patológica/patologia , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Obesidade/patologiaRESUMO
Immunosuppressive elements within the tumor microenvironment are the primary drivers of tumorigenesis and malignant advancement. The presence, as well as the crosstalk between myeloid-derived suppressor cells (MDSCs), osteosarcoma-associated macrophages (OS-Ms), regulatory T cells (Tregs), and endothelial cells (ECs) with osteosarcoma cells cause the poor prognosis of OS. In addition, the consequent immunosuppressive factors favor the loss of treatment potential. Nanoparticles offer a means to dynamically and locally manipulate immuno-nanoparticles, which present a promising strategy for transforming OS-TME. Additionally, chimeric antigen receptor (CAR) technology is effective in combating OS. This review summarizes the essential mechanisms of immunosuppressive cells in the OS-TME and the current immune-associated strategies. The last part highlights the limitations of existing therapies and offers insights into future research directions.