PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR.
EGFR mutations
EMT
lung cancer
metastasis
phospholipase C
resistance to immunotherapy
Journal
Cell reports
ISSN: 2211-1247
Titre abrégé: Cell Rep
Pays: United States
ID NLM: 101573691
Informations de publication
Date de publication:
25 05 2021
25 05 2021
Historique:
received:
27
04
2020
revised:
20
10
2020
accepted:
04
05
2021
entrez:
26
5
2021
pubmed:
27
5
2021
medline:
11
2
2022
Statut:
ppublish
Résumé
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-γ1 (PLC-γ1) to a cytoplasmic motif of PD-L1, which enhances PLC-γ1 activation by EGFR. Once stimulated, PLC-γ1 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
Identifiants
pubmed: 34038737
pii: S2211-1247(21)00526-X
doi: 10.1016/j.celrep.2021.109181
pmc: PMC8170369
pii:
doi:
Substances chimiques
B7-H1 Antigen
0
CD274 protein, human
0
EGFR protein, human
EC 2.7.10.1
ErbB Receptors
EC 2.7.10.1
Type C Phospholipases
EC 3.1.4.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
109181Informations de copyright
Copyright © 2021 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests The authors declare no competing interests.
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