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

Abstract Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1). Leukocyte associated immunoglobulin-like receptor-2 (LAIR-2) is a secreted protein that can act as a deco...

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Published inbioRxiv
Main Authors M Inês Pascoal Ramos, Tian, Linjie, De Ruiter, Emma J, Chang, Song, Paucarmayta, Ana, Singh, Akashdip, Elshof, Eline, Vijver, Saskia V, Shaik, Jahangheer, Bosiacki, Jason, Cusumano, Zachary, Liu, Linda, Langermann, Sol, Willems, Stefan, Flies, Dallas, Linde Meyaard
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 22.10.2020
Subjects
Cancer immunotherapy
Collagen
Extracellular matrix
Fc receptors
Immunoglobulin G
Immunoglobulins
Immunotherapy
Lymphocytes T
Tumors
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Summary:Abstract Collagens are a primary component of the extracellular matrix and are functional ligands for the inhibitory immune receptor leukocyte associated immunoglobulin-like receptor-1 (LAIR-1). Leukocyte associated immunoglobulin-like receptor-2 (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 and that LAIR-2 could release LAIR-1 mediated immune suppression. Analysis of public datasets shows high LAIR-2 expression being associated with a favorable outcome in certain tumors. We designed a dimeric LAIR-2 with a functional IgG1 Fc tail, NC410, and showed that NC410 reduces tumor growth and increases T cell expansion and effector function in humanized tumor models. 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 powerful new strategy for cancer immunotherapy for immune-excluded tumors.
DOI:10.1101/2020.10.21.349480