Targeting glycosylated PD-1 immune checkpoint may be a promising new cancer immunotherapeutic strategy, according to a collaborative study led by Taiwanese researchers, which was reported online in the March 10, 2020, edition of Cancer Research.
The advent of immunotherapies targeting the PD-1 and PD-L1 immune checkpoints represented a major breakthrough in the treatment of cancer.
Expressed on the surface of activated T cells, PD-1 is an inhibitory receptor that dampens T-cell receptor (TCR)/CD28 signaling by engaging with its ligand, PD-L1, which is expressed on the surface of cancer cells.
"Multiple cancer types are currently treated with anti-PD-1 monoclonal antibodies (MAbs), including melanoma, non-small-cell lung cancer (NSCLC), renal cell carcinoma (RCC) and hepatocellular carcinoma (HCC), among others," said lead researcher Mien-Chie Hung, president of the China Medical University (CMU) in Taichung, Taiwan.
"Different cancer types respond differently to PD-1 blockade," noted Hung. "For those cancers with a relative high immunogenicity, such as melanoma, NSCLC, RCC and HCC, the overall response rates range from around 20% to 40%."
Nevertheless, despite that relative clinical success of PD-1 blockade using FDA-approved MAbs such as Keytruda (pembrolizumab, Merck & Co.) and Opdivo (nivolumab, Bristol-Myers Squibb), most cancers do not respond and the underlying regulatory mechanisms of PD-1 are incompletely understood.
The new Cancer Research study was a multi-institutional collaboration among CMU, China's Tianjin Medical University, Stcube Pharmaceuticals and The University of Texas MD Anderson Cancer Center, where Hung was formerly a professor.
"The study showed that PD-1 was extensively N-glycosylated in T cells and that the intensities of its specific glycoforms were altered upon TCR activation," noted Hung.
Initially, "the heterogeneous expression pattern of PD-1 prompted us to investigate the potential involvement of glycosylation, which is an important post-translational modification," he explained.
"Using glycoprotein staining and mass spectrometry, we demonstrated that PD-1 was highly glycosylated," Hung told BioWorld.
"Then, when we removed the glycans or mutated the glycosylated sites on PD-1, we found that its interaction with PD-L1 was significantly decreased, suggesting that glycosylation of PD-1 was essential for mediating its interaction with PD-L1."
Glycosylation was also shown to be critical for maintaining PD-1 protein stability and cell surface localization.
"We then sought to identify more effective approaches to potently block the PD-1 pathway and boost the immune response for sustained patient benefits."
In that regard, said Hung, "we showed that the MAb STM-418 specifically targeted glycosylated PD-1, exhibiting three- to fourfold higher binding affinity to PD-1 than to the FDA-approved PD-1 antibodies nivolumab and pembrolizumab, potently inhibiting PD-L1/PD-1 binding and enhancing antitumor immunity."
Taken together, those findings provide valuable new insights into the functional significance of PD-1 glycosylation and offer a rationale for targeting glycosylated PD-1 as a potential strategy for cancer immunotherapy.
"Our findings also offer novel strategies for designing therapeutic antibodies targeting particular immune checkpoints that are heavily glycosylated,” Hung said.
Looking forward, "we will further explore the therapeutic and diagnostic values of the STM-418 antibody. It will also be of great interest to identify the key glycosyltransferases regulating PD-1 glycosylation, while looking for novel proteins binding with the carbohydrate chains on PD-1."