Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction

Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1....

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Published ineLife Vol. 10
Main Authors Ramos, M Ines Pascoal, Tian, Linjie, de Ruiter, Emma J, Song, Chang, Paucarmayta, Ana, Singh, Akashdip, Elshof, Eline, Vijver, Saskia V, Shaik, Jahangheer, Bosiacki, Jason, Cusumano, Zachary, Jensen, Christina, Willumsen, Nicholas, Karsdal, Morten A, Liu, Linda, Langermann, Sol, Willems, Stefan, Flies, Dallas, Meyaard, Linde
Format Journal Article
LanguageEnglish
Published Cambridge eLife Science Publications, Ltd 14.06.2021
eLife Sciences Publications Ltd
eLife Sciences Publications, Ltd
Subjects
Animal models
Cancer
Cancer Biology
Cancer immunotherapy
Care and treatment
Cell growth
Collagen
Drug therapy
Esophageal cancer
Extracellular matrix
Fc receptors
Immunoglobulin G
Immunotherapy
LAIR1
Liver cancer
Lymphocytes T
Medical prognosis
Ovarian cancer
Proteins
Survival analysis
T cells
tumor
Tumors
Xenografts
Morocco
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Summary:Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte-associated immunoglobulin-like receptor (LAIR)-1. LAIR-2 is a secreted protein that can act as a decoy receptor by binding collagen with higher affinity than LAIR-1. We propose that collagens promote immune evasion by interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1-mediated immune suppression. Analysis of public human datasets shows that collagens, LAIR-1 and LAIR-2 have unique and overlapping associations with survival in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 increases human T cell expansion and effector function in vivo in a mouse xenogeneic-graft versus-host disease model. In humanized mouse tumor models, NC410 reduces tumor growth that is dependent on T cells. Immunohistochemical analysis of human tumors shows that NC410 binds to collagen-rich areas where LAIR-1 + immune cells are localized. Our findings show that NC410 might be a novel strategy for cancer immunotherapy for immune-excluded tumors.
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Department of Pathology and Medical Biology, University Medical Center Groningen, Groningen, The Netherlands.
These authors contributed equally to this work.
These authors also contributed equally to this work.
ISSN:2050-084X
2050-084X
DOI:10.7554/eLife.62927