IL-6-Driven Autocrine Lactate Promotes Immune Escape of Uveal Melanoma.

Purpose: Early metastasis, in which immune escape plays a crucial role, is the leading cause of death in patients with uveal melanoma (UM); however, the molecular mechanism underlying UM immune escape remains unclear, which greatly limits the clinical application of immunotherapy for metastatic UM. Methods: Transcriptome profiles were revealed by RNA-seq analysis. TALL-104 and NK-92MI-mediated cell killing assays were used to examine the immune resistance of UM cells. The glycolysis rate was measured by extracellular acidification analysis. Protein stability was evaluated by CHX-chase assay. Immunofluorescence histochemistry was performed to detect protein levels in clinical UM specimens. Results: Continuous exposure to IL-6 induced the expression of both PD-L1 and HLA-E in UM cells, which promoted UM immune escape. Transcriptome analysis revealed that the expression of most metabolic enzymes in the glycolysis pathway, especially the rate-limiting enzymes, PFKP and PKM, was upregulated, whereas enzymes involved in the acetyl-CoA synthesis pathway were downregulated after exposure to IL-6. Blocking the glycolytic pathway and lactate production by knocking down PKM and LDHA decreased PD-L1 and HLA-E protein, but not mRNA, levels in UM cells treated with IL-6. Notably, lactate secreted by IL-6-treated UM cells was crucial in influencing PD-L1 and HLA-E stability via the GPR81-cAMP-PKA signaling pathway. Conclusions: Our data reveal a novel mechanism by which UM cells acquire an immune-escape phenotype by metabolic reprogramming and reinforce the importance of the link between inflammation and immune escape.

HMGB1 regulates SNAI1 during NSCLC metastasis, both directly, through transcriptional activation, and indirectly, in a RSF1-IT2-dependent manner.

High-mobility group protein B1 (HMGB1) has important functions in cancer cell proliferation and metastasis. However, the mechanisms of HMGB1 function in non-small-cell lung cancer (NSCLC) remain unclear. This study aimed to investigate the underlying mechanism of HMGB1-dependent tumor cell proliferation and NSCLC metastasis. Firstly, we found high HMGB1 expression in NSCLC and showed that HMBG1 promoted proliferation, migration, and invasion of NSCLC cells. HMGB1 could bind to SNAI1 promoter and activate the expression of SNAI1. In addition, HMGB1 could transcriptionally regulate the lncRNA RSF1-IT2. RSF1-IT2 was found to function as ceRNA, sponging miR-129-5p, which targets SNAI1. Notably, HMGB1 was also identified as a target of miR-129-5p, which indicates the establishment of a positive feedback loop. Consequently, high expression of RSF1-IT2 and SNAI1 was found to closely correlate with tumor progression in both HMGB1-overexpressing xenograft nude mice and patients with NSCLC. Taken together, our findings provide new insights into molecular mechanisms of HMGB1-dependent tumor metastasis. Components of the HMGB1-RSF1-IT2-miR-129-5p-SNAI1 pathway may have a potential as prognostic and therapeutic targets in NSCLC.