PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR

Cancer immunotherapy focuses on inhibitors of checkpoint proteins, such as programmed death ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have a generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, intrinsic and microenvironmental factors may be involved. Among all non-immunological signaling pathways surveyed in patients' datasets, EGFR signaling is best associated with high PD-L1 Correspondingly, active EGFRs stabilize PD-L1 transcripts and depletion of PD-L1 severely inhibits EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve the recruitment of phospholipase C-gamma 1 (PLC-gamma 1) to a cytoplasmic motif of PD-L1, which enhances PLC-gamma 1 activation by EGFR. Once stimulated, PLC-gamma 1 activates calcium flux, Rho GTPases, and protein kinase C, collectively promoting an aggressive phenotype. Anti-PD-L1 antibodies can inhibit these intrinsic functions of PD-L1 Our results portray PD-L1 as a molecular amplifier of EGFR signaling and improve the understanding of the resistance of EGFR(+) tumors to immunotherapy.

Automated summary

The research indicates that tumors with EGFR mutations have a lower response to immunotherapy, the EGFR pathway is associated with high PD-L1 expression and can promote an aggressive phenotype, while anti-PD-L1 antibodies can inhibit PD-L1 functions.