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

The following previously published data sets were used

Article and author information

Author details

  1. M Ines Pascoal Ramos

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3644-6517
  2. Linjie Tian

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    Linjie Tian, LT, CS, AP, JS, JB, ZC, LL, SL and DF are employees from Nextcure. Nextcure holds a patent on NC410. (PCT/US20 17/0453 10)..
  3. Emma J de Ruiter

    Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  4. Chang Song

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  5. Ana Paucarmayta

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  6. Akashdip Singh

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5326-8826
  7. Eline Elshof

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  8. Saskia V Vijver

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  9. Jahangheer Shaik

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  10. Jason Bosiacki

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  11. Zachary Cusumano

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  12. Christina Jensen

    Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
    Competing interests
    No competing interests declared.
  13. Nicholas Willumsen

    Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
    Competing interests
    No competing interests declared.
  14. Morten A Karsdal

    Biomarkers and Research, Nordic Bioscience, Herlev, Denmark
    Competing interests
    No competing interests declared.
  15. Linda Liu

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  16. Sol Langermann

    Nextcure, Nextcure, Beltsville, United States
    Competing interests
    No competing interests declared.
  17. Stefan Willems

    Department of Pathology, University Medical Center Utrecht, Utrecht, Netherlands
    Competing interests
    No competing interests declared.
  18. Dallas Flies

    Nextcure, Nextcure, Beltsville, United States
    For correspondence
    fliesd@nextcure.com
    Competing interests
    No competing interests declared.
  19. Linde Meyaard

    Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
    For correspondence
    L.Meyaard@umcutrecht.nl
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-0707-4793

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.

Reviewing Editor

  1. Yuting Ma, Suzhou Institute of Systems Medicine, China

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).

Version history

  1. Received: September 9, 2020
  2. Accepted: June 11, 2021
  3. Accepted Manuscript published: June 14, 2021 (version 1)
  4. Version of Record published: June 24, 2021 (version 2)
  5. Version of Record updated: July 8, 2021 (version 3)

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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  1. M Ines Pascoal Ramos
  2. Linjie Tian
  3. Emma J de Ruiter
  4. Chang Song
  5. Ana Paucarmayta
  6. Akashdip Singh
  7. Eline Elshof
  8. Saskia V Vijver
  9. Jahangheer Shaik
  10. Jason Bosiacki
  11. Zachary Cusumano
  12. Christina Jensen
  13. Nicholas Willumsen
  14. Morten A Karsdal
  15. Linda Liu
  16. Sol Langermann
  17. Stefan Willems
  18. Dallas Flies
  19. Linde Meyaard
(2021)
Cancer immunotherapy by NC410, a LAIR-2 Fc protein blocking human LAIR-collagen interaction
eLife 10:e62927.
https://doi.org/10.7554/eLife.62927

Share this article

https://doi.org/10.7554/eLife.62927

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