Palmitoylation stabilizes PD-L1 to promote breast tumor growth

YI Yang, JM Hsu, L Sun, LC Chan, CW Li, JL Hsu… - Cell research, 2019 - nature.com
YI Yang, JM Hsu, L Sun, LC Chan, CW Li, JL Hsu, Y Wei, W Xia, J Hou, Y Qiu, MC Hung
Cell research, 2019nature.com
Dear Editor, PD-L1 is a well-known transmembrane protein, which is highly expressed on
many types of cancer cells. By binding to its receptor PD-1 on T cells, PD-L1 significantly
inhibits T cells activation and activity, and thus plays a pivotal role in driving the escape of
tumor cells from immune surveillance. 1 Antibody blockade of PD-L1/PD-1 interaction has
revolutionized cancer therapy with promising clinical outcomes in many cancer types,
including melanoma, lung cancer, bladder cancer, colorectal cancer, and renal-cell cancer …
Dear Editor, PD-L1 is a well-known transmembrane protein, which is highly expressed on many types of cancer cells. By binding to its receptor PD-1 on T cells, PD-L1 significantly inhibits T cells activation and activity, and thus plays a pivotal role in driving the escape of tumor cells from immune surveillance. 1 Antibody blockade of PD-L1/PD-1 interaction has revolutionized cancer therapy with promising clinical outcomes in many cancer types, including melanoma, lung cancer, bladder cancer, colorectal cancer, and renal-cell cancer. 2 However, in some others such as prostate cancer, ovarian cancer, and breast cancer, the response rate of PD-L1/PD-1 antibody therapy is less satisfactory. 3 Recent studies have shown that PD-L1 can be regulated by post-translational regulations such as ubiquitination, 4 phosphorylation and glycosylation, 5 providing opportunity for marker-guided effective combinational therapy with immune checkpoint therapy.
Palmitoylation is one of the co-and post-translational modifications of proteins in which a palmitate is covalently linked to a cysteine residue as vast majority via a thioester linkage (also known as S-palmitoylation). 6 By affecting protein membrane anchoring, trafficking, interaction and degradation, palmitoylation plays important roles in human physiological and pathological processes, including cancers. 7, 8 For instance, several cancerrelated proteins, such as EZH2, 9 TEAD, 10 and c-Met, 11 are palmitoylated for stabilization, and knockdown of ZDHHC5, a palmitoyltransferase of EZH2, significantly inhibits glioma tumor growth. 9 Thus, palmitoylation or palmitoyltransferases could be novel targets for cancer therapy. In the current study, we searched for other possible metabolic-related modifications of PD-L1 such as lipid modification, and unexpectedly discovered that palmitoylation occurred on PD-L1 and played an important role in PD-L1 stability. Targeting PD-L1 palmitoylation sensitized tumor cells to T-cell killing and inhibited tumor growth. Previously, we reported that saccharide regulates PD-L1 stability via glycosylation. 5 Recently, lipid modification has also been shown to play an important role in regulation of cell membrane proteins, 12 we were curious whether PD-L1 might also be regulated by lipid modification. Since palmitoylation is an important and broadly studied post-translational lipid modification of proteins, we first explored the possibility whether PD-L1 is regulated by palmitoylation. We treated breast cancer cell lines MDA-MB231 and BT549 with a general palmitoylation inhibitor, 2-bromopalmitate (2-BP). As shown in Fig. 1 a, b, PD-L1 protein level significantly decreased upon 2-BP treatment in a dose-and time-dependent manner, suggesting that PD-L1 expression is regulated by protein palmitoylation. On the basis of prior studies, 9, 11 which indicated that palmitoylation could regulate protein stability, we speculated that PD-L1 itself undergoes palmitoylation to maintain stability. To validate this hypothesis, we subjected PD-L1Flag-expressing
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