11-deoxycortisol positively correlates with T cell immune traits in physiological conditions.

BACKGROUND: Endogenous steroid hormones have significant effects on inflammatory and immune processes, but the immunological activities of steroidogenesis precursors remain largely unexplored. METHODS: We conducted a systematic approach to examine the association between steroid hormones profile and immune traits in a cohort of 534 healthy volunteers. Serum concentrations of steroid hormones and their precursors (cortisol, progesterone, testosterone, androstenedione, 11-deoxycortisol and 17-OH progesterone) were determined by liquid chromatography-tandem mass spectrometry. Immune traits were evaluated by quantifying cellular composition of the circulating immune system and ex vivo cytokine responses elicited by major human pathogens and microbial ligands. An independent cohort of 321 individuals was used for validation, followed by in vitro validation experiments. FINDINGS: We observed a positive association between 11-deoxycortisol and lymphoid cellular subsets numbers and function (especially IL-17 response). The association with lymphoid cellularity was validated in an independent validation cohort. In vitro experiments showed that, as compared to androstenedione and 17-OH progesterone, 11-deoxycortisol promoted T cell proliferation and Candida-induced Th17 polarization at physiologically relevant concentrations. Functionally, 11-deoxycortisol-treated T cells displayed a more activated phenotype (PD-L1high CD25high CD62Llow CD127low) in response to CD3/CD28 co-stimulation, and downregulated expression of T-bet nuclear transcription factor. INTERPRETATION: Our findings suggest a positive association between 11-deoxycortisol and T-cell function under physiological conditions. Further investigation is needed to explore the potential mechanisms and clinical implications. FUNDING: Found in acknowledgements.

Influence of Lenvatinib on the Functional Reprogramming of Peripheral Myeloid Cells in the Context of Non-Medullary Thyroid Carcinoma.

Lenvatinib is a multitarget tyrosine kinase inhibitor (TKI) approved for the treatment of several types of cancers, including metastatic differentiated thyroid cancer (DTC). The intended targets include VEGFR 1-3, FGFR 1-4, PDGFRα, RET, and KIT signaling pathways, but drug resistance inevitably develops and a complete cure is very rare. Recent data has revealed that most of the TKIs have additional 'off-target' immunological effects, which might contribute to a protective antitumor immune response; however, human cellular data are lacking regarding Lenvatinib-mediated immunomodulation in DTC. Here, we investigated in ex vivo models the impact of Lenvatinib on the function of immune cells in healthy volunteers. We found that monocytes and macrophages were particularly susceptible to Lenvatinib, while neutrophiles and lymphocytes were less affected. In tumor-immune cell co-culture experiments, Lenvatinib exerted a broad inhibitory effect on the proinflammatory response in TC-induced macrophages. Interestingly, Lenvatinib-treated cells had decreased cellular M2 membrane markers, whereas they secreted a significantly higher level of the anti-inflammatory cytokine IL-10 upon LPS stimulation. In addition, prolonged exposure to Lenvatinib impaired macrophages survival and phenotypical differentiation, which was accompanied by remarkable morphological changes and suppressed cellular metabolic activity. These effects were mediated by myeloid cell-intrinsic mechanisms which are independent of Lenvatinib's on-target activity. Finally, using specific inhibitors, we argue that dual effects on p38 MAPK and Syk pathways are likely the underlying mechanism of the off-target immunological effects we observed in this study. Collectively, our data show the immunomodulatory properties of Lenvatinib on human monocytes. These insights could be harnessed for the future design of novel treatment strategies involving a combination of Lenvatinib with other immunotherapeutic agents.

Alterations of oral microbiota in Chinese children with viral encephalitis and/or viral meningitis.

The role of oral microbiota in viral encephalitis and/or viral meningitis (VEVM) remains unclear. In this hospital-based, frequency-matched study, children with clinically diagnosed VEVM (n = 68) and those with other diseases (controls, n = 68) were recruited. Their oral swab samples were collected and the oral microbiota was profiled using 16S rRNA gene sequencing. The oral microbiota of children with VEVM exhibited different beta diversity metrics (unweighted UniFrac distance: P < 0.001, R2 = 0.025, Bray-curtis dissimilarity: P = 0.045, R2 = 0.011, and Jaccard dissimilarity: P < 0.001, R2 = 0.017) and higher relative abundances of taxa identified by Linear discriminant analysis (LDA) with effect size (Enterococcus, Pedobacter, Massilia, Prevotella_9, Psychrobacter, Butyricimonas, Bradyrhizobium, etc., LDA scores > 2.0) when compared with the control group. The higher pathway abundance of steroid hormone biosynthesis predicted by oral microbiota was suggested to be linked to VEVM (q = 0.020). Further, a model based on oral microbial traits showed good predictive performance for VEVM with an area under the receiver operating characteristic curve of 0.920 (95% confidence interval: 0.834-1.000). Similar results were also obtained between children with etiologically diagnosed VEVM (n = 43) and controls (n = 68). Our preliminary study identified VEVM-specific oral microbial traits among children, which can be effective in the diagnosis of VEVM.

Kinase Inhibitors' Effects on Innate Immunity in Solid Cancers.

Innate immune cells constitute a plastic and heterogeneous cell population of the tumor microenvironment. Because of their high tumor infiltration and close interaction with resident tumor cells, they are compelling targets for anti-cancer therapy through either ablation or functionally reprogramming. Kinase inhibitors (KIs) that target aberrant signaling pathways in tumor proliferation and angiogenesis have been shown to have additional immunological effects on myeloid cells that may contribute to a protective antitumor immune response. However, in patients with malignancies, these effects are poorly described, warranting meticulous research to identify KIs' optimal immunomodulatory effect to support developing targeted and more effective immunotherapy. As many of these KIs are currently in clinical trials awaiting approval for the treatment of several types of solid cancer, we evaluate here the information on this drug class's immunological effects and how such mechanisms can be harnessed to improve combined treatment regimens in cancer.