TY - JOUR
T1 - Notch-dependent cooperativity between myeloid lineages promotes Langerhans cell histiocytosis pathology
AU - Kvedaraite, Egle
AU - Milne, Paul
AU - Khalilnezhad, Ahad
AU - Chevrier, Marion
AU - Sethi, Raman
AU - Lee, Hong Kai
AU - Hagey, Daniel W.
AU - von Bahr Greenwood, Tatiana
AU - Mouratidou, Natalia
AU - Jädersten, Martin
AU - Lee, Nicole Yee Shin
AU - Minnerup, Lara
AU - Tan, Yingrou
AU - Dutertre, Charles Antoine
AU - Benac, Nathan
AU - Hwang, You Yi
AU - Lum, Josephine
AU - Loh, Amos Hong Pheng
AU - Jansson, Jessica
AU - Teng, Karen Wei Weng
AU - Khalilnezhad, Shabnam
AU - Xu, Weili
AU - Resteu, Anastasia
AU - Tey, Hong Liang
AU - Guan, Ng Lai
AU - Larbi, Anis
AU - Howland, Shanshan Wu
AU - Arnell, Henrik
AU - Andaloussi, Samir E.L.
AU - Braier, Jorge
AU - Rassidakis, Georgios
AU - Galluzzo, Laura
AU - Dzionek, Andrzej
AU - Henter, Jan Inge
AU - Chen, Jinmiao
AU - Collin, Matthew
AU - Ginhoux, Florent
N1 - Publisher Copyright:
Copyright © 2022 The Authors, some rights reserved;
PY - 2022/12/1
Y1 - 2022/12/1
N2 - Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
AB - Langerhans cell histiocytosis (LCH) is a potentially fatal neoplasm characterized by the aberrant differentiation of mononuclear phagocytes, driven by mitogen-activated protein kinase (MAPK) pathway activation. LCH cells may trigger destructive pathology yet remain in a precarious state finely balanced between apoptosis and survival, supported by a unique inflammatory milieu. The interactions that maintain this state are not well known and may offer targets for intervention. Here, we used single-cell RNA-seq and protein analysis to dissect LCH lesions, assessing LCH cell heterogeneity and comparing LCH cells with normal mononuclear phagocytes within lesions. We found LCH discriminatory signatures pointing to senescence and escape from tumor immune surveillance. We also uncovered two major lineages of LCH with DC2- and DC3/monocyte-like phenotypes and validated them in multiple pathological tissue sites by high-content imaging. Receptor-ligand analyses and lineage tracing in vitro revealed Notch-dependent cooperativity between DC2 and DC3/monocyte lineages during expression of the pathognomonic LCH program. Our results present a convergent dual origin model of LCH with MAPK pathway activation occurring before fate commitment to DC2 and DC3/monocyte lineages and Notch-dependent cooperativity between lineages driving the development of LCH cells.
UR - http://www.scopus.com/inward/record.url?scp=85144589732&partnerID=8YFLogxK
U2 - 10.1126/SCIIMMUNOL.ADD3330
DO - 10.1126/SCIIMMUNOL.ADD3330
M3 - Article
C2 - 36525505
AN - SCOPUS:85144589732
SN - 2470-9468
VL - 7
JO - Science Immunology
JF - Science Immunology
IS - 78
M1 - eadd3330
ER -