MCT4 Upregulates PD-L1 Expression and Defines Novel Composite Therapeutic Targets for Triple-Negative Breast Cancer

Immune checkpoint blocking therapy targeting the PD-1/PD-L1 axis has shown promising availability for triple-negative breast cancer (TNBC). Nevertheless, in some cases, targeting efficiency is low and efficient gene interaction networks need to be sought, which inspired the exploration that MCT4 and PD-L1 co-expression network analysis and potential regulatory mechanism research. In the paper, bioinformatics, Western blot, qRT-PCR, flow cytometry, biochemical analysis, multiple immunohistochemistry, CRISPR/Cas9 and lentiviral transduction for MCT4 knockout (sgMCT4/231 KO) or overexpression (pEGFP-N1-MCT4/231) were adopted. Analysis of database basis showed MCT4 (SLC16A3) and PD-L1 (CD274) were functionally correlated and highly expressed in TNBC cells, further MCT4 and PD-L1 were co-expressed (more than 50% PD-L1+MCT4+ cells) in tissue section of TNBC patients. The expression of PD-L1 in TNBC cell lines MDA-MB-231, MDA-MB-468 and BT-549 was sensitive to lactate concentration, and lowering MCT4 expression could downregulate PD-L1 expression through affecting the lactate concentration. These data suggests that MCT4 is positively associated with PD-L1 and the co-targeted therapy for TNBC may be a promising clinical treatment strategy.