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Updated: Jun 29, 2025
Implantation and Evaluation of Melanoma in the Murine Choroid via Optical Coherence Tomography
Published on: December 2, 2022
IL-6-Driven Autocrine Lactate Promotes Immune Escape of Uveal Melanoma
Chaoju Gong1, Meiling Yang1, Huirong Long1,2
1Xuzhou Key Laboratory of Ophthalmology, The Affiliated Xuzhou Municipal Hospital of Xuzhou Medical University, Xuzhou First People's Hospital, Eye Institute of Xuzhou, Xuzhou, China.
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.
