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PD-L1 Recruits Phospholipase C and Enhances EGFR Signaling: Relevance to Resistance of EGFR-Mutated Lung Tumors to Immunotherapy
- Source :
- SSRN Electronic Journal.
- Publication Year :
- 2020
- Publisher :
- Elsevier BV, 2020.
-
Abstract
- Cancer immunotherapy has focused on inhibitors of checkpoint proteins, such as Programmed Death Ligand 1 (PD-L1). Unlike RAS-mutated lung cancers, EGFR mutant tumors have generally low response to immunotherapy. Because treatment outcomes vary by EGFR allele, we assumed that intrinsic and microenvironmental factors are involved. Among all non-immunological signaling pathways we surveyed in patients’ datasets, EGFR signaling best associated with high PD-L1. Correspondingly, active EGFRs stabilized PD-L1’s transcripts and depleting PD-L1 severely inhibited EGFR-driven tumorigenicity and metastasis in mice. The underlying mechanisms involve physical recruitment of an auto-inhibited phospholipase C-g1 (PLC-g1) to PD-L1, which enhances trans-phosphorylation by EGFR. Once activated, pPLC-g1 stimulates calcium flux, RHO GTPases and protein kinase C, thereby establishing an aggressive mesenchymal phenotype. We show that approved 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 lay the foundation for understanding resistance of EGFR mutant tumors to immunotherapy.
Details
- ISSN :
- 15565068
- Database :
- OpenAIRE
- Journal :
- SSRN Electronic Journal
- Accession number :
- edsair.doi...........24e412d36a3883d66efc870c0685b489