Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction
- University Medical Center Utrecht, Netherlands
- Nextcure, United States
- Nordic Bioscience, Denmark
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 interacting with LAIR-1 expressed on immune cells, and that LAIR-2 releases LAIR-1 mediated immune suppression. Analysis of public human datasets show 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.
Data availability
Source codes were provided for Figure 1, Figure 2 and Supplemental Figure 1
Article and author information
Author details
M Ines Pascoal Ramos
Funding
Nederlandse Organisatie voor Wetenschappelijk Onderzoek (Vici 918.15.608)
- Linde Meyaard
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Ethics
Animal experimentation: All mouse studies were performed at NextCure based on Institutional Animal Care and Use Committee standards according to the protocols of NextCure Animal (NCA) Study 164 (NCA#164 for Figure 3), NCA#122 (for Figure 4), NCA#209 (for Figure 5), NCA#217 (for Figure 6) and NCA#270 (for Supplementary Figure 3).
Human subjects: Peripheral Blood Mononuclear Cells (PBMCs) were isolated from blood of healthy donors in agreement with ethical committee of the University Medical Center Utrecht (UMCU) and after written informed consent from the subjects in accordance with the Declaration of Helsinki.Specimens of seven selected tumor types were included for analysis: head and neck squamous cell carcinoma (HNSC), glioblastoma (GBM), melanoma, non-small-cell lung carcinoma (NSCLC), high-grade serous carcinoma (HGSC), pancreatic ductal adenocarcinoma (PDAC), and stomach adenocarcinoma (STAD). Of each tumor type, in agreement with the ethical committee of the UMCU, formalin fixed, paraffin embedded (FFPE) material of 9-10 tumor specimens and five healthy specimens was collected from the tissue biobank (research protocol 17-786).
Copyright
© 2021, Ramos et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction
eLife 10:e62927.
https://doi.org/10.7554/eLife.62927
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