Lymph node stromal cells (LNSCs) regulate immunity through constructing lymphocyte niches. LNSC-produced laminin α5 (Lama5) regulates CD4⁺ T cells but the underlying mechanisms of its functions are poorly understood. Here we show that depleting Lama5 in LNSCs resulted in decreased Lama5 protein in the LN cortical ridge (CR) and around high endothelial venules (HEVs). Lama5 depletion affected LN structure with increased HEVs, upregulated chemokines, and cell adhesion molecules, and led to greater numbers of Tregs in the T cell zone. Mouse and human T cell transendothelial migration and T cell entry into LNs were suppressed by Lama5 through the receptors α6 integrin and α-dystroglycan. During immune responses and allograft transplantation, depleting Lama5 promoted antigen-specific CD4⁺ T cell entry into the CR through HEVs, suppressed T cell activation, and altered T cell differentiation to suppressive regulatory phenotypes. Enhanced allograft acceptance resulted from depleting Lama5 or blockade of T cell Lama5 receptors. Lama5 and Lama4/Lama5 ratios in allografts were associated with the rejection severity. Overall, our results demonstrated that stromal Lama5 regulated immune responses through altering LN structures and T cell behaviors. This study delineated a stromal Lama5–T cell receptor axis that can be targeted for immune tolerance modulation.

Octamer-binding transcription factor 4 (Oct4) has been recently implicated as a proangiogenic regulator in several induced pluripotent stem cells (iPSCs), however, its role in cancer stem-like cells (CSCs) remain unclear. We report here that Oct4 participates in tumor vasculogenesis in liver CSCs (LCSCs). We identify that LCSCs possess the potential of endothelial trans-differentiation under endothelial induction, present endothelial specific markers and their functions in vitro, and participate in neovasculogenesis in vivo. The knockdown of the Oct4A by short hairpin RNA (shRNA) in LCSCs represses endothelial trans-differentiation potential, but induces endothelial lineage-restricted differentiation, the latter is positively regulated by Oct4B1. Furthermore, Oct4 regulates vasculogenesis in LCSCs may be via the AKT-NF-κB-p65 signaling pathway. This work reveals Oct4, which is a crucial regulator, plays a critical role in tumor endothelial-like cells transition of LCSCs through Oct4A and Oct4B1 by different ways. The simultaneous inhibition of both the isoforms of Oct4 is hence expected to help regress neovascularization derived from CSCs. Our findings may provide insights to the possible new mechanisms of tumor vasculogenesis for primary liver cancer.

Myeloma (MM) is a malignant plasma cell disorder, which is incurable owing to its drug resistance. Autophagy performs an integral function in homeostasis, survival, and drug resistance in multiple myeloma (MM). Therefore, the purpose of the present research was to identify potential autophagy-related genes (ARGs) in patients with MM. We downloaded the transcriptomic data (GSE136400) of patients with MM, as well as the corresponding clinical data from the Gene Expression Omnibus (GEO); the patients were classified at random into two groups in a ratio of 6: 4, with 212 samples in the training dataset and 142 samples in the test dataset. Both multivariate and univariate Cox regression analyses were performed to identify autophagy-related genes. The univariate Cox regression analysis demonstrated that 26 ARGs had a significant correlation with overall survival (OS). We constructed an autophagy-related risk prognostic model based on six ARGs: EIF2AK2 (ENSG00000055332), KIF5B (ENSG00000170759), MYC (ENSG00000136997), NRG2 (ENSG00000158458), PINK1 (ENSG00000158828), and VEGFA (ENSG00000112715) using LASSO-Cox regression analysis to predict risk outcomes, which revealed substantially shortened OS duration in the high-risk cohort in contrast with that in the low-risk cohort. Therefore, the ARG-based model significantly predicted the MM patients’ prognoses and was verified in an internal test set. Differentially expressed genes were found to be predominantly enriched in pathways associated with inflammation and immune regulation. Immune infiltration of tumor cells resulted in the formation of a strong immunosuppressive microenvironment in high-risk patients. The potential therapeutic targets of ARGs were subsequently analyzed via protein–drug network analysis. Therefore, a prognostic model for MM was established via a comprehensive analysis of ARGs, through using the clinical models; we have further revealed the molecular landscape features of multiple myeloma.