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

• Main Authors: M Ines Pascoal Ramos, Linjie Tian, Emma J de Ruiter, Chang Song, Ana Paucarmayta, Akashdip Singh, Eline Elshof, Saskia V Vijver, Jahangheer Shaik, Jason Bosiacki, Zachary Cusumano, Christina Jensen, Nicholas Willumsen, Morten A Karsdal, Linda Liu, Sol Langermann, Stefan Willems, Dallas Flies, Linde Meyaard
• Format: Article
• Language: English
• Published: eLife Sciences Publications Ltd 2021-06-01
• Series: eLife
• Subjects: tumor; collagen; LAIR1
• Online Access: https://elifesciences.org/articles/62927

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.