Anti-TNFSF18 monoclonal antibody, clone YGL386

Fibroblast-like synoviocytes (FLS) are major contributors to joint inflammation in rheumatoid arthritis (RA). Forkhead box O 3 (FOXO3) perturbations in immune cells are increasingly linked to RA pathogenesis. Here, we show that FOXO3 is distinctly inactivated/phosphorylated in the FLS of rheumatoid synovitis. In vitro, stimulation of FLS with tumor necrosis factor-alpha alpha (TNF alpha) induced a rapid and sustained inactivation of FOXO3. mRNA profiling revealed that the inactivation of FOXO3 is important for the sustained pro-inflammatory interferon response to TNF alpha (CXCL9, CXCL10, CXCL11, and TNFSF18). Mechanistically, our studies demonstrate that the inactivation of FOXO3 results from TNF-induced downregulation of phosphoinositide-3-kinase-interacting protein 1 (PIK3IP1). Thus, we identified FOXO3 and its modulator PIK3IP1 as a critical regulatory circuit for the inflammatory response of the resident mesenchymal cells to TNF alpha and contribute insight into how the synovial tissue brings about chronic inflammation that is driven by TNF alpha.

Objective: To understand the immune molecular landscapes of the two major costimulatory and coinhibitory pathways (B7 and TNPR families) in oral squamous cell carcinoma. Methods: The B7 family members (CD80, CD86, CD274, ICOSLG, CD276, VTCN1, NCR-3LG1, HHLA2 and PDCD1LG2) and INFRfamily members (TNFSF4, CD40, CD70, TNFSF9, TNFRSF14 and TNFSF18) were used to analyse the costimulatory and coinhibikny pathway alterations in oral squamous cell carcinoma. The online tools UCSC Xena and cBioPortal were used to derive oral squamous cell carcinoma patients'clinical parameters, mRNA levels, mutations, DNA copy number alterations and methylation levels. The correlations between mRNA levels and methylation levels were determined using Spearman correlation analysis. A Kaplan Meier survival analysis was performed to examine the relationships between mRNA expression levels and overall survival. Results: Compared with normal oral epithelial tissues, approximately 23.1% of patients showed upregulation of B7 expression and 15.3% showed upregulation of TNFR expression in oral squamous cell carcinoma, with CD274 (PD-L1) upregulation being the most common alteration. Mutations and copy number alterations were shown to have little effect on B7 and TNFR expression. The mRNA levels of B7 and TNFR genes were negatively correlated with their methylation levels. Furthermore, oral squamous cell carcinoma patients with high expression levels of CD274 showed poor overall survival, while those with high expression levels of CD276 or HHLA2 showed good clinical outcomes. Conclusion: This study elucidated the molecular landscapes of the B7 and TNFR genes in oral squamous cell carcinoma, which could provide a novel strategy for clinical therapy.