Resumen
Triple-negative breast cancer (TNBC) is an aggressive disease that responds in a limited manner to immune checkpoint blockades targeting the PD-L1/PD-1 axis, suggesting that PD-L1 potentiates TNBC progression via pathways not related to immune suppression. We demonstrated that, in human breast cancer cells, PD-L1 expression increased in a cell-autonomous manner tumor cell growth, invasion and release of pro-metastatic factors; these activities were elevated by exposure to PD-1 and were markedly impaired in S283-mutated PD-L1-expressing cells. Invasion of WT-PD-L1-expressing TNBC cells depended on autocrine chemokine circuits, involving CXCR1/2, CCR2, CCR5 and their ligands. In T cell-deficient mice, WT-PD-L1 exhibited increased tumor growth and metastasis by TNBC cells, whereas S283A-PD-L1-expressing cells showed a very poor tumorigenic and metastatic profile. These findings on cell-autonomous and PD-1-induced pro-metastatic activities of PD-L1 in cancer cells suggest that treatments targeting PD-L1 could improve the efficacy of immune-targeting checkpoint inhibitors, e.g., anti-PD-1 or anti-CTLA-4 in TNBC.