The ubiquitin E3 ligase FBXO22 degrades PD-L1 and sensitizes cancer cells to DNA damage
Menée à l'aide de lignées de cellules cancéreuses (poumon, sein et côlon), cette étude met en évidence un mécanisme par lequel l'ubiquitine ligase E3 FBOX22 dégrade le ligand PD-L1 et sensibilise les cellules cancéreuses aux dommages causés à l'ADN
Lung cancer is the leading cause of cancer-related deaths in the United States. PD-L1 is often overexpressed on cancer cells, driving immune-independent, cell-intrinsic functions that increase resistance to DNA-damaging therapies such as IR or cisplatin. FBXO22, a known ubiquitin E3 ligase, decreases the level of PD-L1 in NSCLC cells and increases their sensitivity to DNA-damaging therapies. Furthermore, targeting cyclin-dependent kinase 5 (CDK5), which is highly expressed in NSCLC, increases FBXO22 levels, leading to decreased expression of PD-L1. Thus, we identify an innovative strategy for treating NSCLC by targeting CDK5 to enhance the efficacy of immunotherapy alone or in combination with DNA-damaging therapies.High expression of programmed death-ligand 1 (PD-L1) in cancer cells drives immune-independent, cell-intrinsic functions, leading to resistance to DNA-damaging therapies. We find that high expression of the ubiquitin E3 ligase FBXO22 sensitizes nonsmall cell lung cancer (NSCLC) cells to ionizing radiation (IR) and cisplatin, and that activation of FBXO22 by phosphorylation is necessary for this function. Importantly, FBXO22 activates PD-L1 ubiquitination and degradation, which in turn increases the sensitivity of NSCLC cells to DNA damage. Cyclin-dependent kinase 5 (CDK5), aberrantly active in cancer cells, plays a crucial role in increasing the expression of PD-L1 in medulloblastoma [R. D. Dorand et al., Science 353, 399–403 (2016)]. We show in NSCLC cells that inhibiting CDK5 or reducing its expression increases the level of FBXO22, decreases that of PD-L1, and increases the sensitivity of the cells to DNA damage. We conclude that FBXO22 is a substrate of CDK5, and that inhibiting CDK5 reduces PD-L1 indirectly by increasing FBXO22. Pairing inhibitors of CDK5 with immune checkpoint inhibitors may increase the efficacy of immune checkpoint blockade alone or in combination with DNA-damaging therapies.