Targeting the glucocorticoid receptor-CCR8 axis mediated bone marrow T cell sequestration enhances infiltration of anti-tumor T cells in intracranial cancers.

Brain tumors such as glioblastomas are resistant to immune checkpoint blockade therapy, largely due to limited T cell infiltration in the tumors. Here, we show that mice bearing intracranial tumors exhibit systemic immunosuppression and T cell sequestration in bone marrow, leading to reduced T cell infiltration in brain tumors. Elevated plasma corticosterone drives the T cell sequestration via glucocorticoid receptors in tumor-bearing mice. Immunosuppression mediated by glucocorticoid-induced T cell dynamics and the subsequent tumor growth promotion can be abrogated by adrenalectomy, the administration of glucocorticoid activation inhibitors or glucocorticoid receptor antagonists, and in mice with T cell-specific deletion of glucocorticoid receptor. CCR8 expression in T cells is increased in tumor-bearing mice in a glucocorticoid receptor-dependent manner. Additionally, chemokines CCL1 and CCL8, the ligands for CCR8, are highly expressed in bone marrow immune cells in tumor-bearing mice to recruit T cells. These findings suggested that brain tumor-induced glucocorticoid surge and CCR8 upregulation in T cells lead to T cell sequestration in bone marrow, impairing the anti-tumor immune response. Targeting the glucocorticoid receptor-CCR8 axis may offer a promising immunotherapeutic approach for the treatment of intracranial tumors.

The first mitogenomic phylogenetic framework of Dorcus sensu lato (Coleoptera: Lucanidae), with an emphasis on generic taxonomy in Eastern Asia.

BACKGROUND: Dorcus stag beetles in broad sense are one of the most diverse group in Lucanidae and important saproxylic insects playing a crucial role in nutrient recycling and forest biomonitoring. However, the dazzling morphological differentiations have caused numerous systematic confusion within the big genus, especially the puzzlingly generic taxonomy. So far, there is lack of molecular phylogenetic study to address the chaotic situation. In this study, we undertook mitochondrial genome sequencing of 42 representative species including 18 newly-sequenced ones from Eastern Asia and reconstructed the phylogenetic framework of stag beetles in Dorcus sensu lato for the first time. RESULTS: The mitogenome datasets of Dorcus species have indicated the variable mitogenomic lengths ranged from 15,785 to 19,813 bp. Each mitogenome contained 13 PCGs, 2 rRNAs, 22 tRNAs, and a control region, and all PCGs were under strong purifying selection (Ka/Ks < 1). Notably, we have identified the presence of a substantial intergenic spacer (IGS) between the trnAser (UCN) and NAD1 genes, with varying lengths ranging from 129 bp (in D. hansi) to 158 bp (in D. tityus). The mitogenomic phylogenetic analysis of 42 species showed that Eastern Asia Dorcus was monophyletic, and divided into eight clades with significant genetic distance. Four of them, Clade VIII, VII, VI and I are clustered by the representative species of Serrognathus Motschulsky, Kirchnerius Schenk, Falcicornis Séguy and Dorcus s.s. respectively, which supported their fully generic positions as the previous morphological study presented. The topology also showed the remaining clades were distinctly separated from the species of Dorcus sensu lato, which implied that each of them might demonstrate independent generic status. The Linnaeus nomenclatures were suggested as Eurydorcus Didier stat. res., Eurytrachellelus Didier stat. res., Hemisodorcus Thomson stat. res. and Velutinodorcus Maes stat. res. For Clade V, IV, III and II respectively. CONCLUSION: This study recognized the monophyly of Dorcus stag beetles and provided a framework for the molecular phylogeny of this group for the first time. The newly generated mitogenomic data serves as a valuable resource for future investigations on lucanid beetles. The generic relationship would facilitate the systematics of Dorcus stag beetles and thus be useful for exploring their evolutionary, ecological, and conservation aspects.

SOD2 promotes the immunosuppressive function of mesenchymal stem cells at the expense of adipocyte differentiation.

The potent immunomodulatory function of mesenchymal stem/stromal cells (MSCs) elicited by proinflammatory cytokines IFN-γ and TNF-α (IT) is critical to resolve inflammation and promote tissue repair. However, little is known about how the immunomodulatory capability of MSCs is related to their differentiation competency in the inflammatory microenvironment. In this study, we demonstrate that the adipocyte differentiation and immunomodulatory function of human adipose tissue-derived MSCs (MSC(AD)s) are mutually exclusive. Mitochondrial reactive oxygen species (mtROS), which promote adipocyte differentiation, were decreased in MSC(AD)s due to IT-induced upregulation of superoxide dismutase 2 (SOD2). Furthermore, knockdown of SOD2 led to enhanced adipogenic differentiation but reduced immunosuppression capability of MSC(AD)s. Interestingly, the adipogenic differentiation was associated with increased mitochondrial biogenesis and upregulation of peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PPARGC1A/PGC-1α) expression. IT inhibited PGC-1α expression and decreased mitochondrial mass but promoted glycolysis in an SOD2-dependent manner. MSC(AD)s lacking SOD2 were compromised in their therapeutic efficacy in DSS-induced colitis in mice. Taken together, these findings indicate that the adipogenic differentiation and immunomodulation of MSC(AD)s may compete for resources in fulfilling the respective biosynthetic needs. Blocking of adipogenic differentiation by mitochondrial antioxidant may represent a novel strategy to enhance the immunosuppressive activity of MSCs in the inflammatory microenvironment.