RESUMO
Shifting the balance away from tumor-mediated immune suppression toward tumor immune rejection is the conceptual foundation for a variety of immunotherapy efforts currently being tested. These efforts largely focus on activating antitumor immune responses but are confounded by multiple immune cell populations, including myeloid-derived suppressor cells (MDSCs), which serve to suppress immune system function. We have identified immune-suppressive MDSCs in the brains of GBM patients and found that they were in close proximity to self-renewing cancer stem cells (CSCs). MDSCs were selectively depleted using 5-flurouracil (5-FU) in a low-dose administration paradigm, which resulted in prolonged survival in a syngeneic mouse model of glioma. In coculture studies, patient-derived CSCs but not nonstem tumor cells selectively drove MDSC-mediated immune suppression. A cytokine screen revealed that CSCs secreted multiple factors that promoted this activity, including macrophage migration inhibitory factor (MIF), which was produced at high levels by CSCs. Addition of MIF increased production of the immune-suppressive enzyme arginase-1 in MDSCs in a CXCR2-dependent manner, whereas blocking MIF reduced arginase-1 production. Similarly to 5-FU, targeting tumor-derived MIF conferred a survival advantage to tumor-bearing animals and increased the cytotoxic T cell response within the tumor. Importantly, tumor cell proliferation, survival, and self-renewal were not impacted by MIF reduction, demonstrating that MIF is primarily an indirect promoter of GBM progression, working to suppress immune rejection by activating and protecting immune suppressive MDSCs within the GBM tumor microenvironment. Stem Cells 2016;34:2026-2039.
Assuntos
Neoplasias Encefálicas/imunologia , Glioblastoma/imunologia , Evasão da Resposta Imune , Fatores Inibidores da Migração de Macrófagos/metabolismo , Células Supressoras Mieloides/metabolismo , Células-Tronco Neoplásicas/metabolismo , Animais , Arginase/metabolismo , Neoplasias Encefálicas/patologia , Carcinogênese/metabolismo , Carcinogênese/patologia , Linhagem Celular Tumoral , Sobrevivência Celular/efeitos dos fármacos , Meios de Cultivo Condicionados/farmacologia , Feminino , Glioblastoma/patologia , Humanos , Evasão da Resposta Imune/efeitos dos fármacos , Camundongos Endogâmicos C57BL , Camundongos Nus , Células Supressoras Mieloides/efeitos dos fármacos , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/patologia , Microambiente Tumoral/efeitos dos fármacosRESUMO
INTRODUCTION: Gastric cancer is one of the common malignant tumors with a high incidence and mortality in China. Prognostic biomarkers and potential predictors of the treatment efficacy of gastric cancer urgently need to be identified. Integrin-ß (ITGB) is a superfamily of integrins and is involved in cell adhesion, tissue repair, immune response, and tumor metastasis. METHODS: We analyzed ITGB1 expression in our hospital samples of the gastric cancer cohort. And the public data of The Cancer Genome Atlas stomach adenocarcinoma (TCGA-STAD), The Asian Cancer Research Group (ACRG)/GSE62254, and GSE15459 data sets were analyzed by using the bioinformatic methods. The relationships between ITGB1 expression and clinicopathological features, patient prognosis, activation of the Wnt/ß-catenin signaling pathway, and tumor immunosuppressive factors were also explored. RESULTS: The positive rate of ITGB1 expression in the Fudan University Shanghai Cancer Center gastric cancer tumor tissues was 61.4% (258/420) and correlated with deep invasion (p = 0.017), an advanced clinical stage (p = 0.011), and a poor prognosis (p < 0.05). The TCGA-STAD/ACRG/GSE15459 cohorts also showed similar results. ITGB1 is one of the upstream molecules of the Wnt/ß-catenin signaling pathway and is correlated with tumor immune suppression. In gastric cancer, we found a correlation between ITGB1 expression and Wnt/ß-catenin signaling pathway activity. In the TCGA-STAD/ACRG/GSE15459 cohorts, ITGB1 expression was positively associated with immunosuppressive factors and negatively associated with immunoactive factors. Patients with low ITGB1 expression exhibited a significantly high immunotherapy response ratio according to an analysis of tumor immune dysfunction and exclusion (TIDE), which may indicate that ITGB1 is a potential predictor of immunotherapy efficacy. CONCLUSIONS: ITGB1 affects the prognosis in gastric cancer patients and plays a core role in immune suppression in gastric cancer.
Assuntos
Adenocarcinoma , Neoplasias Gástricas , Humanos , Prognóstico , Neoplasias Gástricas/patologia , China/epidemiologia , Via de Sinalização Wnt , Adenocarcinoma/patologia , BiomarcadoresRESUMO
The chemokine CXCL8 has been found to play an important role in tumor progression in recent years. CXCL8 activates multiple intracellular signaling pathways by binding to its receptors (CXCR1/2), and plays dual pro-tumorigenic roles in the tumor microenvironment (TME) including directly promoting tumor survival and affecting components of TME to indirectly facilitate tumor progression, which include facilitating tumor cell proliferation and epithelial-to-mesenchymal transition (EMT), pro-angiogenesis, and inhibit anti-tumor immunity. More recently, clinical trials indicate that CXCL8 can act as an independently predictive biomarker in patients receiving immune checkpoint inhibitions (ICIs) therapy. Preclinical studies also suggest that combined CXCL8 blockade and ICIs therapy can enhance the anti-tumor efficacy, and several clinical trials are being conducted to evaluate this therapy modality.
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Phototherapy and immunogenic cell death (ICD) are powerful strategies to fight cancer. However, their therapeutic outcomes are diminished by immunosuppressive and hypoxia microenvironment. Herein, a photo-based, immunomodulating and hypoxia-alleviated nanosystem, PDA-ICG@CAT-DTA-1, is proposed to achieve the synergism between phototherapy and immunotherapy. Catalase (CAT) and anti-GITR antibody (DTA-1) are loaded to photothermal agent and photosensitizer composed PDA-ICG nanoparticles. The PDA-ICG@CAT-DTA-1 exhibits intrinsic local hyperthermia and enhanced ROS generation in tumor, and abrogates tumor immune suppression. It results in reduction of intratumoral FOXP3+ regulatory T cells (4.3-fold) and increase of CD4+ effector T cells (1.5-fold) compare with the control, and promotes damage associated molecular patterns generation to reinvigorate ICD effect. The potent antitumor of PDA-ICG@CAT-DTA-1 is proved in 4T1 bilateral tumor-bearing mice, with inhibition ratio of 95.1% for primary cancers and 68.7% for abscopal cancers. Our findings highlight great promise of the constructed versatility nanosystem to fix bottlenecks for cancer therapy.
Assuntos
Hipertermia Induzida , Nanopartículas , Neoplasias , Animais , Linhagem Celular Tumoral , Morte Celular Imunogênica , Imunoterapia , Camundongos , Neoplasias/tratamento farmacológico , FototerapiaRESUMO
Malignant metastasis is the most important cause of death in breast cancer (BC) patients, while the lung is a major inflammation and metastatic target organ. Exosomes are nano-sized vesicles that could be uptaken by resident cells to generate the pre-metastatic niche before tumor cells preferentially motility. In the present study, we demonstrated that high expression of C-C motif chemokine ligand 2 (CCL2) in lung could recruit the myeloid-derived suppressor cells (MDSCs) and contribute to the establishment of microenvironment. CCL2 provided recruitment of immune cells under carcinomas conditions and inflammatory responses. We also developed the novel mice model for specific over-expressing CCL2 in the lung, and verified that the BC organotropic metastasis was not because of the enhanced tumor cell proliferation, but the regulatory expression of CCL2 in the target organ. To better explore the crosstalk of exosomal molecules and CCL2 in host tissue, we constructed the "education" lung by exosomes intravenous injection and determined the prominent exosome-uptake by alveolar epithelial type II cells in vivo. Furthermore, we identified the exosomal microRNA-200b-3p could bind to PTEN, which may involved in the regulation of AKT/NF-κB/CCL2 cascades. Therefore, our study suggest that CCL2 expression in the lung was regulated by BC-derived exosomal microRNA, which primed the pre-metastastatic niche and may be a prognostic marker for the development of BC lung metastasis.
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MicroRNAs (miRNAs) play an important role in tumorigenesis, but their role in tumor-induced immune suppression is largely unknown. STAT3 signaling, a key pathway mediating immune suppression in the tumor microenvironment, is responsible for the transcription of several important miRNAs. In this study, we observed that miR-146a, a known important regulator of immune responses, was downregulated by blocking activated STAT3 in hepatocellular carcinoma (HCC) cells. Furthermore, miR-146a inhibition in HCC cells not only altered the STAT3 activation-associated cytokine profile but also reversed HCC-induced NK cell dysfunction in vitro and improved the anti-tumor effect of lymphocytes in vivo. Importantly, ChIP and luciferase reporter assays confirmed that STAT3 directly bound to the miR-146a promoter and induced miR-146a expression. These findings indicated that miR-146a expression was regulated by aberrantly activated STAT3 in HCC cells and exerted negative effects on anti-tumor immune response, which resulted in the upregulation of cytokines such as TGF-ß, IL-17, VEGF and downregulation of type I IFN to create an immunosuppressive microenvironment. This further insight into understanding the mechanism responsible for tumor-induced immune suppression highlights the potential application of miR-146a as a novel immunotherapeutic target for HCC.
Assuntos
MicroRNAs/metabolismo , Animais , Carcinoma Hepatocelular/patologia , Carcinoma Hepatocelular/terapia , Linhagem Celular Tumoral , Sobrevivência Celular , Células Hep G2 , Humanos , Interferon Tipo I/metabolismo , Interleucina-17/metabolismo , Neoplasias Hepáticas/patologia , Neoplasias Hepáticas/terapia , Linfócitos/citologia , Linfócitos/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , MicroRNAs/antagonistas & inibidores , MicroRNAs/genética , Oligonucleotídeos Antissenso , Fator de Transcrição STAT3/antagonistas & inibidores , Fator de Transcrição STAT3/genética , Fator de Transcrição STAT3/metabolismo , Transfecção , Fator de Crescimento Transformador beta/metabolismo , Transplante Heterólogo , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
Ligation of GITR (glucocorticoid-induced tumor necrosis factor (TNF) receptor-related gene, or TNFRSF18) by agonist antibody has recently entered into early phase clinical trials for the treatment of advanced malignancies. Although the ability of GITR modulation to induce tumor regression is well-documented in preclinical studies, the underlying mechanisms of action, particularly its effects on CD4(+)foxp3(+) regulatory T cells (Treg), have not been fully elucidated. We have previously demonstrated that GITR ligation in vivo by agonist antibody DTA-1 causes a >50% reduction of intra-tumor Treg with down modulation of Foxp3 expression. Here we show that the loss of Foxp3 is tumor-dependent. Adoptively-transferred Foxp3(+)Treg from tumor-bearing animals lose Foxp3 expression in the host when treated with DTA-1, whereas Treg from naïve mice maintain Foxp3 expression. GITR ligation also alters the expression of various transcription factors and cytokines important for Treg function. Complete Foxp3 loss in intra-tumor Treg correlates with a dramatic decrease in Helios expression and is associated with the upregulation of transcription factors T-Bet and Eomes. Changes in Helios correspond with a reduction in IL-10 and an increase in IFNγ expression in DTA-1-treated Treg. Together, these data show that GITR agonist antibody alters Treg lineage stability inducing an inflammatory effector T cell phenotype. The resultant loss of lineage stability causes Treg to lose their intra-tumor immune suppressive function, making the tumor susceptible to killing by tumor-specific effector CD8(+) T cells.