Targeting TGF-β1 pathway might be a promising approach to enhance immune checkpoint blockade PD-1/PD-L1 in nasopharyngeal carcinoma

A group from Department of Otolaryngology-Head and Neck Surgery, Nanfang Hospital, Southern Medical University, Guangzhou, China, etc. has reported that targeting TGF-β1 pathway might be a promising approach to enhance immune checkpoint blockade PD-1/PD-L1 in nasopharyngeal carcinoma (NPC).
https://pubmed.ncbi.nlm.nih.gov/35311117/

It is well known that PD-L1, programmed death ligand-1, is a transmembrane glycoprotein expressed by tumor cells and PD-L1 inhibits T cells activity and promotes immune evasion through binding to its receptor PD-1 on T cells.

TGF-β is a multifunctional cytokine with an important role in both physiologic and pathologic processes, including cancer. The aberrantly upregulated production of TGF-β has been strongly implicated in tumor progression, angiogenesis, and metastasis, as well as immune escape. TGF-β has been regarded as a critical immunosuppressive cytokine, which suppresses the antitumor activity of effector cells, including CD8+ T cells, natural killer (NK) cells, and macrophages.

In this study, it was confirmed that PD-L1 was heavily glycosylated in NPC, and found that TGF-β1 played an important role in N-glycosylation of PD-L1.
Inhibition of TGF-β1 by a TGF-β type I receptor inhibitor (SB431542) reduced not only PD-L1 expression but also PD-L1 glycosylation. The reduction of PD-L1 glycosylation was confirmed by loss of PD-L1 binding ability to ConA lectin.

Authors found that the glycosylation of PD-L1 was affected by TGF-β1 through c-Jun/STT3A signaling pathway, suggesting that targeting TGF-β1 pathway might be a promising approach to enhance immune checkpoint blockade in NPC avoiding deglycosylatin of PD-L1.

Co-culture of NPC cells (5-8F cells) and Jurkat T cells, conducted with STT3A-knockdown (shSTT3Acells), SB431542 and tunicamycin (TM) pretreatments on T cells.