Cancer immunotherapy by nc410, a lair-2 fc protein blocking human lair-collagen interaction
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
(2021) eLife, volume 10, pp. 1 - 29
(Article)
Abstract
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
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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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Keywords: Animals, Antineoplastic Agents, Immunological, Cell Line, Tumor, Collagen/metabolism, Computational Biology, Humans, Immunoglobulin Fc Fragments/genetics, Immunoglobulin G/genetics, Immunotherapy/methods, Mice, Neoplasms/therapy, Receptors, Immunologic/genetics, Recombinant Fusion Proteins/genetics, Xenograft Model Antitumor Assays, General Biochemistry,Genetics and Molecular Biology, General Immunology and Microbiology, General Neuroscience, Research Support, Non-U.S. Gov't, Journal Article
ISSN: 2050-084X
Publisher: eLife Sciences Publications
Note: Funding Information: Dutch Research Council (NWO) Vici 918.15.608 Linde Meyaard. Publisher Copyright: © Ramos et al. © 2021, Ramos et al.
(Peer reviewed)