Nuclear PD-L1 promotes cell cycle progression of BRAF-mutated colorectal cancer by inhibiting THRAP3

Colorectal cancers (CRCs) with the BRAF V600E mutation exhibit upregulation of programmed death ligand 1 (PD-L1) but fail to respond to immunotherapy targeting programmed cell death protein 1 (PD-1)/PD-L1. Recent studies have explored the intracellular functions of PD-L1. Here, we demonstrate that PD-L1 was highly expressed in both the cytoplasm and nucleus of BRAF-mutated CRC tumor cells and tissues. Nuclear PD-L1 (nPDL1) promoted the growth of tumor cells both in vitro and in vivo. Mechanistic investigations revealed that PD-L1 translocation into the nucleus was facilitated by the binding of p-ERK. Further, nPD-L1 upregulated the expression of cell cycle regulator BUB1 via interactions with thyroid hormone receptor-associated protein 3 (THRAP3), thereby accelerating cell cycle progression and promoting cell proliferation. Moreover, BRAF V600Emutated CRC cells exhibited upregulation of PD-L1 expression via the transcription factor LEF-1. These findings reveal a novel role of nPD-L1, which promotes cell cycle progression in an immune-independent manner in BRAF V600E-mutated CRC. Our study provides novel insight into the mechanisms underlying BRAF V600E-mutated CRC progression.

Automated summary

Colorectal cancers with the BRAF V600E mutation have upregulated PD-L1 expression. This study found that PD-L1 is highly expressed in both the nucleus and cytoplasm. In the nucleus, PD-L1 translocation is facilitated by p-ERK and it interacts with THRAP3 to upregulate BUB1 expression, thus accelerating cell cycle progression and promoting cell proliferation. Additionally, BRAF V600E mutated CRC cells upregulate PD-L1 expression via the transcription factor LEF-1. These findings reveal a novel role of nPD-L1 in promoting cell cycle progression in an immune-independent manner in BRAF V600E mutated CRC.