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Background
Glutamine addiction is a hallmark of clear cell renal cell carcinoma (ccRCC); yet whether glutamine metabolism impacts local immune surveillance is unclear. This knowledge may yield novel immunotherapeutic opportunities.Objective
To seek a potential therapeutic target in glutamine-addicted ccRCC.Design, setting, and participants
Tumors from ccRCC patients from a Shanghai cohort and ccRCC tumor data from The Cancer Genome Atlas (TCGA) cohort were analyzed. In vivo and in vitro studies were conducted with fresh human ccRCC tumors and murine tumor cells.Outcome measurements and statistical analysis
Immune cell numbers and functions were analyzed by flow cytometry. Glutamine and cytokine concentrations were determined. Survival was compared between different subpopulations of patients using Kaplan-Meier and Cox regression analyses.Results and limitations
We found that in ccRCC, high interleukin (IL)-23 expression was significantly associated with poor survival in both TCGA (overall survival [OS] hazard ratio [HR] = 2.04, cancer-specific survival [CSS] HR = 2.95; all p < 0.001) and Shanghai (OS HR = 2.07, CSS HR = 3.92; all p < 0.001) cohorts. IL-23 blockade prolongs the survival of tumor-bearing mice, promotes T-cell cytotoxicity in in vitro cultures of human ccRCC tumors, and augments the therapeutic benefits of anti-PD-1 antibodies. Mechanistically, glutamine consumption by ccRCC tumor cells results in the local deprivation of extracellular glutamine, which induces IL-23 secretion by tumor-infiltrating macrophages via the activation of hypoxia-inducible factor 1α (HIF1α). IL-23 activates regulatory T-cell proliferation and promotes IL-10 and transforming growth factor β expression, thereby suppressing tumor cell killing by cytotoxic lymphocytes. The positive correlations between glutamine metabolism, IL-23 levels, and Treg responses are confirmed in both TCGA cohort and tumors from Shanghai ccRCC patients. Study limitations include the unclear impacts of glutamine deprivation and IL-23 on other immune cells.Conclusions
Macrophage-secreted IL-23 enhanced Treg functions in glutamine-addicted tumors; thus, IL-23 is a promising target for immunotherapy in ccRCC.Patient summary
In this study, we analyzed the immune components in glutamine-addicted clear cell renal cell carcinoma (ccRCC) tumors from two patient cohorts and conducted both in vitro and in vivo studies. We found that ccRCC tumor cell-intrinsic glutamine metabolism orchestrates immune evasion via interleukin (IL)-23, and IL-23–high patients had significantly poorer survival than IL-23–low patients. IL-23 should thus be considered a therapeutic target in ccRCC, either alone or in combination with immune checkpoint inhibitors. 相似文献Methods In total, 220 patients with stroke were recruited to complete the scale. The reliability of the SSCI was evaluated using internal consistency and test–retest methods. Exploratory factor analysis (EFA) was conducted to identify domains of the SSCI. Convergent validity was determined by analyzing the correlation between SSCI scores, activities of daily living (ADL) and depression.
Results Construct validity was determined by factor analysis, extracting three factors with eigenvalues greater than 1, explaining 30.5%, 25.7%, and 8.5% of the variance, respectively, and accounting for 64.8% of the variance. All items had factor loadings above 0.40. The first factor comprised questions related to ‘self-stigma’ (items 1–13). The second (items 14–22) and third (items 23–24) factors aggregated questions related to ‘enacted stigma’. In terms of convergent validity, the SSCI total scale was moderately correlated to the Barthel Index (BI) and the Self-rating Depression Scale (SDS). Cronbach’s alpha value (internal reliability) for the total SSCI score was 0.949, and the intraclass correlation coefficient value (test-retest reliability) was 0.802.
Discussion The results provide initial evidence that the SSCI is a reliable and validated measure for evaluating stigma in stroke patients in China. 相似文献
Cellular arachidonic acid (AA), an unsaturated fatty acid found ubiquitously in plasma membranes, is metabolized to different prostanoids, such as prostacyclin (PGI2) and prostaglandin E2 (PGE2), by the three-step reactions coupling the upstream cyclooxygenase (COX) isoforms (COX-1 and COX-2) with the corresponding individual downstream synthases. While the vascular actions of these prostanoids are well-characterized, their specific roles in the hippocampus, a major brain area for memory, are poorly understood. The major obstacle for its understanding in the brain was to mimic the biosynthesis of each prostanoid. To solve the problem, we utilized Single-Chain Hybrid Enzyme Complexes (SCHECs), which could successfully control cellular AA metabolites to the desired PGI2 or PGE2. Our in vitro studies suggested that neurons with higher PGI2 content and lower PGE2 content exhibited survival protection and resistance to Amyloid-β-induced neurotoxicity. Further extending to an in vivo model, the hybrid of PGI2-producing transgenic mice and Alzheimer’s disease (AD) mice showed restored long-term memory. These findings suggested that the vascular prostanoids, PGI2 and PGE2, exerted significant regulatory influences on neuronal protection (by PGI2), or damage (by PGE2) in the hippocampus, and raised a concern that the wide uses of aspirin in cardiovascular diseases may exert negative impacts on neurodegenerative protection.
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