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 Geiger; Eytan Ruppin; Yosef Yarden

doi:10.1016/j.celrep.2021.109181

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 Geiger

Eytan Ruppin, Yosef Yarden

Bar-Ilan University - Azrieli Faculty of Medicine

Weizmann Institute of Science
University of Maryland, College Park
National Institutes of Health
Hebrew University of Jerusalem
University of California at Los Angeles
Ben-Gurion University of the Negev

Research output: Contribution to journal › Article › peer-review

32 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 language	English
Article number	109181
Journal	Cell Reports
Volume	35
Issue number	8
DOIs	https://doi.org/10.1016/j.celrep.2021.109181
State	Published - 25 May 2021

Bibliographical note

Publisher Copyright:
© 2021 The Author(s)

Funding

We thank Tomer Meir Salame for experimental help and Julian Downwards for sharing plasmids. Y.Y. is the incumbent of the Harold and Zelda Goldenberg Professorial Chair in Molecular Cell Biology. Our studies have been supported by the Israel Science Foundation (ISF), the Israel Cancer Research Fund (ICRF), the European Research Council (ERC), and the Dr. Miriam and Sheldon G. Adelson Medical Research Foundation .

Funders	Funder number
National Cancer Institute	ZIABC011803
Israel Cancer Research Fund
Dr. Miriam and Sheldon G. Adelson Medical Research Foundation
Horizon 2020 Framework Programme	740469
European Commission
Israel Science Foundation

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Keywords

EGFR mutations
EMT
lung cancer
metastasis
phospholipase C
resistance to immunotherapy

Access to Document

10.1016/j.celrep.2021.109181

Cite this

Ghosh, S., Nataraj, N. B., Noronha, A., Patkar, S., Sekar, A., Mukherjee, S., Winograd-Katz, S., Kramarski, L., Verma, A., Lindzen, M., Garcia, D. D., Green, J., Eisenberg, G., Gil-Henn, H., Basu, A., Lender, Y., Weiss, S., Oren, M., Lotem, M., ... Yarden, Y. (2021). PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR. Cell Reports, 35(8), Article 109181. https://doi.org/10.1016/j.celrep.2021.109181

@article{09e764596ff94f069c7249c1cae418ee,

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

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{\textquoteright} 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.",

keywords = "EGFR mutations, EMT, lung cancer, metastasis, phospholipase C, resistance to immunotherapy",

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

note = "Publisher Copyright: {\textcopyright} 2021 The Author(s)",

year = "2021",

month = may,

day = "25",

doi = "10.1016/j.celrep.2021.109181",

language = "אנגלית",

volume = "35",

journal = "Cell Reports",

issn = "2211-1247",

publisher = "Elsevier BV",

number = "8",

}

Ghosh, S, Nataraj, NB, Noronha, A, Patkar, S, Sekar, A, Mukherjee, S, Winograd-Katz, S, Kramarski, L, Verma, A, Lindzen, M, Garcia, DD, Green, J, Eisenberg, G, Gil-Henn, H, Basu, A, Lender, Y, Weiss, S, Oren, M, Lotem, M, Geiger, B, Ruppin, E & Yarden, Y 2021, 'PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR', Cell Reports, vol. 35, no. 8, 109181. https://doi.org/10.1016/j.celrep.2021.109181

TY - JOUR

T1 - PD-L1 recruits phospholipase C and enhances tumorigenicity of lung tumors harboring mutant forms of EGFR

AU - Ghosh, Soma

AU - Nataraj, Nishanth Belugali

AU - Noronha, Ashish

AU - Patkar, Sushant

AU - Sekar, Arunachalam

AU - Mukherjee, Saptaparna

AU - Winograd-Katz, Sabina

AU - Kramarski, Lior

AU - Verma, Aakanksha

AU - Lindzen, Moshit

AU - Garcia, Diana Drago

AU - Green, Joseph

AU - Eisenberg, Galit

AU - Gil-Henn, Hava

AU - Basu, Arkaprabha

AU - Lender, Yan

AU - Weiss, Shimon

AU - Oren, Moshe

AU - Lotem, Michal

AU - Geiger, Benjamin

AU - Ruppin, Eytan

AU - Yarden, Yosef

PY - 2021/5/25

Y1 - 2021/5/25

N2 - 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.

AB - 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.

KW - EGFR mutations

KW - EMT

KW - lung cancer

KW - metastasis

KW - phospholipase C

KW - resistance to immunotherapy

UR - https://www.scopus.com/pages/publications/85106489367

U2 - 10.1016/j.celrep.2021.109181

DO - 10.1016/j.celrep.2021.109181

M3 - ???researchoutput.researchoutputtypes.contributiontojournal.article???

C2 - 34038737

AN - SCOPUS:85106489367

SN - 2211-1247

VL - 35

JO - Cell Reports

JF - Cell Reports

IS - 8

M1 - 109181

ER -

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

Abstract

Bibliographical note

Funding

UN SDGs

Keywords

Access to Document

Other files and links

Fingerprint

Cite this