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

Soma Ghosh, Nishanth Belugali Nataraj, Ashish Noronha, Sushant Patkar, Arunachalam Sekar, Saptaparna Mukherjee, Sabina Winograd-Katz, Lior Kramarski, Aakanksha Verma, Moshit Lindzen, Diana Drago Garcia, Joseph Green, Galit Eisenberg, Hava Gil-Henn, Arkaprabha Basu, Yan Lender, Shimon Weiss, Moshe Oren, Michal Lotem, Benjamin GeigerEytan Ruppin, Yosef Yarden

Research output: Contribution to journalArticlepeer-review

23 Scopus citations

Abstract

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+ tumors to immunotherapy.

Original languageEnglish
Article number109181
JournalCell Reports
Volume35
Issue number8
DOIs
StatePublished - 25 May 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Keywords

  • EGFR mutations
  • EMT
  • lung cancer
  • metastasis
  • phospholipase C
  • resistance to immunotherapy

Fingerprint

Dive into the research topics of 'PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR'. Together they form a unique fingerprint.

Cite this