SUMMARY Dendritic cells (DCs) orchestrate the initiation, programming, and regulation of anti-tumor immune responses. Emerging evidence indicates that the tumor microenvironment (TME) induces immune dysfunctional tumor-infiltrating DCs (TIDCs), characterized with both increased intracellular lipid content and mitochondrial respiration. The underlying mechanism, however, remains largely unclear. Here, we report that fatty acid-carrying tumor-derived exosomes (TDEs) induce immune dysfunctional DCs to promote immune evasion. Mechanistically, peroxisome proliferator activated receptor (PPAR) α responds to the fatty acids delivered by TDEs, resulting in excess lipid droplet biogenesis and enhanced fatty acid oxidation (FAO), culminating in a metabolic shift toward mitochondrial oxidative phosphorylation, which drives DC immune dysfunction. Genetic depletion or pharmacologic inhibition of PPARα effectively attenuates TDE-induced DC-based immune dysfunction and enhances the efficacy of immunotherapy. This work uncovers a role for TDE-mediated immune modulation in DCs and reveals that PPARα lies at the center of metabolic-immune regulation of DCs, suggesting a potential immunotherapeutic target.
BackgroundTargeting the TGF-β1 pathway for breast cancer metastasis therapy has become an attractive strategy. We have previously demonstrated that naringenin significantly reduced TGF-β1 levels in bleomycin-induced lung fibrosis and effectively prevented pulmonary metastases of tumors. This raised the question of whether naringenin can block TGF-β1 secretion from breast cancer cells and inhibit their pulmonary metastasis.MethodsWe transduced a lentiviral vector encoding the mouse Tgf-β1 gene into mouse breast carcinoma (4T1-Luc2) cells and inoculated the transformant cells (4T1/TGF-β1) into the fourth primary fat pat of Balb/c mice. Pulmonary metastases derived from the primary tumors were monitored using bioluminescent imaging. Spleens, lungs and serum (n = 18–20 per treatment group) were analyzed for immune cell activity and TGF-β1 level. The mechanism whereby naringenin decreases TGF-β1 secretion from breast cancer cells was investigated at different levels, including Tgf-β1 transcription, mRNA stability, translation, and extracellular release.ResultsIn contrast to the null-vector control (4T1/RFP) tumors, extensive pulmonary metastases derived from 4T1/TGF-β1 tumors were observed. Administration of the TGF-β1 blocking antibody 1D11 or naringenin showed an inhibition of pulmonary metastasis for both 4T1/TGF-β1 tumors and 4T1/RFP tumors, resulting in increased survival of the mice. Compared with 4T1/RFP bearing mice, systemic immunosuppression in 4T1/TGF-β1 bearing mice was observed, represented by a higher proportion of regulatory T cells and myeloid-derived suppressor cells and a lower proportion of activated T cells and INFγ expression in CD8+ T cells. These metrics were improved by administration of 1D11 or naringenin. However, compared with 1D11, which neutralized secreted TGF-β1 but did not affect intracellular TGF-β1 levels, naringenin reduced the secretion of TGF-β1 from the cells, leading to an accumulation of intracellular TGF-β1. Further experiments revealed that naringenin had no effect on Tgf-β1 transcription, mRNA decay or protein translation, but prevented TGF-β1 transport from the trans-Golgi network by inhibiting PKC activity.ConclusionsNaringenin blocks TGF-β1 trafficking from the trans-Golgi network by suppressing PKC activity, resulting in a reduction of TGF-β1 secretion from breast cancer cells. This finding suggests that naringenin may be an attractive therapeutic candidate for TGF-β1 related diseases.Electronic supplementary materialThe online version of this article (doi:10.1186/s13058-016-0698-0) contains supplementary material, which is available to authorized users.
Radiation-induced lung injury (RILI) is the main complication of radiotherapy for thoracic malignancies. Since naringenin, a potent immune-modulator, has been found to relieve bleomycin-induced lung fibrosis by restoring the balance of disordered cytokines, we sought to determine whether naringenin would mitigate RILI and to investigate the underlying mechanism. Animals received fractionated irradiation in the thoracic area to induce RILI. Enzyme-linked immunosorbent assay and MILLIPLEX assays were used for serum and bronchoalveolar lavage fluid for cytokine analyses, hematoxylin and eosin staining for pathologic changes, and Masson trichrome staining for determination of lung fibrosis. Interleukin (IL)-1 was found significantly elevated after thoracic irradiation and it triggered production of profibrotic tumor growth factor both in vivo and in vitro, suggesting the vital role of in IL-1 in the development of RILI. Furthermore, we found that naringenin was able to ameliorate RILI through downregulation of IL-1 and restoration of the homeostasis of inflammatory factors. Our results demonstrated that naringenin could serve as a potent immune-modulator to ameliorate RILI. More importantly, we suggest that a new complementary strategy of maintaining the homeostasis of inflammatory factors combined with radiation could improve the efficacy of thoracic radiotherapy.
IMPORTANCE Emerging research suggests that factors associated with the built environment, including artificial light, air pollution, and noise, may adversely affect children's mental health, while living near green space may reduce stress. Little is known about the combined roles of these factors on children's stress. OBJECTIVE To investigate associations between components of the built environment with personal and home characteristics in a large cohort of children who were assessed for perceived stress. DESIGN, SETTING, AND PARTICIPANTS In this cohort study, a total of 2290 Southern California Children's Health Study participants residing in 8 densely populated urban communities responded to detailed questionnaires. Exposures of artificial light at night (ALAN) derived from satellite observations, near-roadway air pollution (NRP) determined from a dispersion model, noise estimated from the US Traffic Noise Model, and green space from satellite observations of the enhanced vegetation index were linked to each participant's geocoded residence. MAIN OUTCOMES AND MEASURES Children's stress was assessed at ages 13 to 14 years and 15 to 16 years using the 4-item Perceived Stress Scale (PSS-4), scaled from 0 to 16, with higher scores indicating greater perceived stress. Measurements were conducted in 2010 and 2012, and data were analyzed from February 6 to August 24, 2019. Multivariate mixed-effects models were used to examine multiple exposures; modification and mediation analyses were also conducted. RESULTS Among the 2290 children in this study, 1149 were girls (50%); mean (SD) age was 13.5 (0.6) years. Girls had significantly higher perceived stress measured by PSS-4 (mean [SD] score, 5.7 [3.4]) than boys (4.9 [3.2]). With increasing age (from 13.5 [0.6] to 15.3 [0.6] years), the mean PSS-4 score rose from 5.6 (3.3) to 6.0 (3.4) in girls but decreased for boys from 5.0 (3.2) to 4.7 (3.1). Multivariate mixed-effects models examining multiple exposures indicated that exposure to secondhand smoke in the home was associated with a 0.85 (95% CI, 0.46-1.24) increase in the PSS-4 score. Of the factors related to the physical environment, an interquartile range (IQR) increase in ALAN was associated with a 0.57 (95% CI, 0.05-1.09) unit increase in the PSS-4 score together with a 0.16 score increase per IQR increase of near-roadway air pollution (95% CI, 0.02-0.30) and a −0.24 score decrease per IQR increase of the enhanced vegetation index (95% CI, −0.45 to −0.04). Income modified the ALAN effect size estimate; participants in households earning less than $48 000 per year had significantly greater stress per IQR increase in ALAN. Sleep duration partially mediated the associations between stress and both enhanced vegetation index (17%) and ALAN (18%). CONCLUSIONS AND RELEVANCE In this cohort study, children's exposure to smoke at home in addition to residential exposure to ALAN and near-roadway air pollution were associated with increased perceived stress among young adolescent children. These associations appeared to be pa...
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