PD-L1 Exon 3 Is a Hidden Switch of Its Expression and Function in Oral Cancer Cells

Abstract

The interaction between programmed cell death 1 ligand 1 (PD-L1) and programmed cell death protein 1 (PD-1) protects tumor cells from immune surveillance. PD-L1 exon 3 is a potential alternative exon and encodes an Ig variable (IgV) domain. Here, we found that a lack of exon 3 leads to the significant loss of cellular membrane locations and the dramatically reduced protein expression of PD-L1, indicating that PD-L1 exon 3 is essential for its protein expression and translocation to the cell membrane. Notably, oral cancer cells show almost no exon 3 skipping to ensure the expression of the full-length, functional PD-L1 protein. We discovered two key exonic splicing enhancers (ESEs) for exon 3 inclusion. Two efficient antisense oligonucleotides (ASOs) were identified to block these two ESEs, which can significantly trigger exon 3 skipping and decrease the production of full-length, functional PD-L1 on the surface of cancer cells. Treatment of oral cancer cells with these ASOs significantly enhanced immune cells’ suppression of cancer cell proliferation. Surprisingly, these two ASOs also significantly inhibited cell growth and induced cell pyroptosis in oral cancer cells. Altogether, the results of our study demonstrate the pivotal roles of exon 3 in PD-L1 expression and provide a novel anti-PD-L1 method.

Exploring beyond Common Cell Death Pathways in Oral Cancer: A Systematic Review

“…Among the selected studies, 46 studies evaluated ferroptosis , 22 studies focused on pyroptosis [28,33,[64][65][66][67][68][69][70][71][72][73][74][75][76][77][78][79][80][81][82][83], 8 studies on necroptosis [84][85][86][87][88][89][90][91] and 5 studies on other types of cell death [92][93][94][95][96]. One study [28] explored both ferroptosis and pyroptosis, Among the selected studies, 46 studies evaluated ferroptosis , 22 studies focused on pyroptosis [28,33,[64][65][66][67][68][69][70][71][72][73]…”

“…Pyroptosis, an inflammatory type of caspase-mediated cell death, can modulate the immunogenic potential of specific cancers [82]. The role of pyroptosis in OSCC is an area of ongoing research, and the mechanisms and implications are not fully understood, but there is evidence to suggest that pyroptosis may play a role in both development and progression of OSCC [76][77][78][79][80][81][82][83]. Pyroptosis derives its name from the combination of "pyro" and "ptosis".…”