Non-cytomembrane PD-L1: An atypical target for cancer

Abstract

Programmed death ligand 1 (PD-L1) has conventionally been considered as a type I transmembrane protein that can interact with its receptor, programmed cell death 1 (PD-1), thus inducing T cell deactivation and immune escape. However, targeting the PD-1/PD-L1 axis has achieved adequate clinical responses in very few specific malignancies. Recent studies have explored the extracellularly and subcellularly located PD-L1, namely, nuclear PD-L1 (nPD-L1), cytoplasmic PD-L1 (cPD-L1), soluble PD-L1 (sPD-L1), and extracellular vesicle PD-L1 (EV PD-L1), which might shed light on the resistance to anti-PD1/PDL1 therapy. In this review, we summarize the four atypical localizations of PD-L1 with a focus on their novel functions, such as gene transcription regulation, therapeutic efficacy prediction, and resistance to various cancer therapies. Additionally, we highlight that non-cytomembrane PD-L1s are of significant cancer diagnostic value and are promising therapeutic targets to treat cancer.

Keywords: Actinomycin D (PubChem CID: 457193); BMS-1001 (PubChem CID: 145925650); BMS-1166 (PubChem CID: 118434635); Cancer target; Cytoplasmic PD-L1; Daunorubicin (PubChem CID: 30323); Doxorubicin (PubChem CID: 31703); Epirubicin (PubChem CID: 41867); Extracellular vesicle PD-L1; H1A (PubChem CID: 101144265); Non-cytomembrane PD-L1; Nuclear PD-L1; Santacruzamate A (PubChem CID: 72946782); Soluble PD-L1.