Pyruvate Kinase M2 Is Required for the Expression of the Immune Checkpoint PD-L1 in Immune Cells and Tumors

• Published in: Frontiers in immunology Vol. 8; p. 1300
• Main Authors: Palsson-McDermott, Eva M., Dyck, Lydia, Zasłona, Zbigniew, Menon, Deepthi, McGettrick, Anne F., Mills, Kingston H. G., O’Neill, Luke A.
• Format: Journal Article
• Language: English
• Published: Switzerland Frontiers Media S.A 13.10.2017
• Subjects: dendritic cells; Immunology; LPS; macrophages; PD-L1; pyruvate kinase isoform M2; tumor cells; hypoxia-inducible factor 1α; macrophages; pyruvate kinase isoform M2; dendritic cells; PD-L1; tumor cells; LPS
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2017.01300

Blocking interaction of the immune checkpoint receptor PD-1 with its ligand PD-L1 is associated with good clinical outcomes in a broad variety of malignancies. High levels of PD-L1 promote tumor growth by restraining CD8 T-cell responses against tumors. Limiting PD-L1 expression and function is therefore critical for allowing the development of antitumor immune responses and effective tumor clearance. Pyruvate kinase isoform M2 (PKM2) is also a key player in regulating cancer as well as immune responses. PKM2 catalyzes the final rate-limiting step of glycolysis. Furthermore, PKM2 as a dimer translocates to the nucleus, where it stimulates hypoxia-inducible factor 1α (Hif-1α) transactivation domain function and recruitment of p300 to the hypoxia response elements (HRE) of Hif-1α target genes. Here, we provide the first evidence of a role for PKM2 in regulating the expression of PD-L1 on macrophages, dendritic cells (DCs), T cells, and tumor cells. LPS-induced expression of PD-L1 in primary macrophages was inhibited by the PKM2 targeting compound TEPP-46. Furthermore, RNA silencing of PKM2 inhibited LPS-induced PD-L1 expression. This regulation occurs through direct binding of PKM2 and Hif-1α to HRE sites on the PD-L1 promoter. Moreover, TEPP-46 inhibited expression of PD-L1 on macrophages, DCs, and T cells as well as tumor cells in a mouse CT26 cancer model. These findings broaden our understanding of how PKM2 may contribute to tumor progression and may explain the upregulation of PD-L1 in the tumor microenvironment.