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
Further reading
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- Cancer Biology
Why does a normal cell possibly harboring genetic mutations in oncogene or tumor suppressor genes becomes malignant and develops a tumor is a subject of intense debate. Various theories have been proposed but their experimental test has been hampered by the unpredictable and improbable malignant transformation of single cells. Here, using an optogenetic approach we permanently turn on an oncogene (KRASG12V) in a single cell of a zebrafish brain that, only in synergy with the transient co-activation of a reprogramming factor (VENTX/NANOG/OCT4), undergoes a deterministic malignant transition and robustly and reproducibly develops within 6 days into a full-blown tumor. The controlled way in which a single cell can thus be manipulated to give rise to cancer lends support to the ‘ground state theory of cancer initiation’ through ‘short-range dispersal’ of the first malignant cells preceding tumor growth.
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- Cancer Biology
Most human pancreatic ductal adenocarcinoma (PDAC) are not infiltrated with cytotoxic T cells and are highly resistant to immunotherapy. Over 90% of PDAC have oncogenic KRAS mutations, and phosphoinositide 3-kinases (PI3Ks) are direct effectors of KRAS. Our previous study demonstrated that ablation of Pik3ca in KPC (KrasG12D; Trp53R172H; Pdx1-Cre) pancreatic cancer cells induced host T cells to infiltrate and completely eliminate the tumors in a syngeneic orthotopic implantation mouse model. Now, we show that implantation of Pik3ca−/− KPC (named αKO) cancer cells induces clonal enrichment of cytotoxic T cells infiltrating the pancreatic tumors. To identify potential molecules that can regulate the activity of these anti-tumor T cells, we conducted an in vivo genome-wide gene-deletion screen using αKO cells implanted in the mouse pancreas. The result shows that deletion of propionyl-CoA carboxylase subunit B gene (Pccb) in αKO cells (named p-αKO) leads to immune evasion, tumor progression, and death of host mice. Surprisingly, p-αKO tumors are still infiltrated with clonally enriched CD8+ T cells but they are inactive against tumor cells. However, blockade of PD-L1/PD1 interaction reactivated these clonally enriched T cells infiltrating p-αKO tumors, leading to slower tumor progression and improve survival of host mice. These results indicate that Pccb can modulate the activity of cytotoxic T cells infiltrating some pancreatic cancers and this understanding may lead to improvement in immunotherapy for this difficult-to-treat cancer.
