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

Ramos, M I; Tian, Linjie; Ruiter, Emma J. de; 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 M.; Flies, Dallas B.; Meyaard, Linde

doi:10.7554/elife.62927

Cited by 54 publications

(41 citation statements)

References 68 publications

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“…Here, we have shown that MMP generated collagen fragments cause immunomodulation through LAIR-1, potentially mediating T cell immunosuppression both in the TME and in the circulation. These findings further strengthen LAIR-1 as a promising therapeutic target to improve cancer treatment and overall survival (26,33,37). Previously, we showed that LAIR-2-Fc can revert collagen-induced LAIR-1 mediated immunosuppression, resulting in decreased tumor outgrowth in humanized mouse models (33).…”

Section: Discussionsupporting

confidence: 55%

“…These findings further strengthen LAIR-1 as a promising therapeutic target to improve cancer treatment and overall survival (26,33,37). Previously, we showed that LAIR-2-Fc can revert collagen-induced LAIR-1 mediated immunosuppression, resulting in decreased tumor outgrowth in humanized mouse models (33). Therefore, LAIR-2-Fc is currently being evaluated in a clinical trial (NCT04408599).…”

Section: Discussionmentioning

confidence: 54%

“…To prevent immunosuppression through LAIR-1, the interaction with its ligandcollagenmust be prevented by blocking either the receptor or the ligand. As previously described, dimeric LAIR-2-Fc proteins are able to block LAIR-1-collagen interactions, resulting in decreased tumor outgrowth in humanized mouse models (33,37).…”

Section: Lair-1 Binding and Signaling By Collagen I Fragments Is Blocked By Lair-2 Fusion Proteinsmentioning

confidence: 66%

“…Increased tumor collagen and LAIR-1 mRNA expression are associated with worse overall survival (33). The collagen fragment C1M is generated from collagen I by MMP1 and MMP9 mediated cleavage and these MMPs are frequently overexpressed by tumors (16).…”

Section: Poor Overall Survival Of Cancer Patients With High Mmp Collagen I and Lair-1 Expressionmentioning

confidence: 99%

“…Fc and LAIR-2-Fc dead are effective blockers of LAIR-1 activation by full-length collagen(33). LAIR-2-Fc, with a functional IgG1 Fc-tail, and LAIR-2-Fc dead, with a silenced IgG1 Fc-tail, both bound to mock treated and fragmented collagen I, with increased binding of LAIR-2-Fc dead compared to LAIR-2-Fc (Figures5A, B).…”

mentioning

confidence: 96%

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Collagen Fragments Produced in Cancer Mediate T Cell Suppression Through Leukocyte-Associated Immunoglobulin-Like Receptor 1

et al. 2021

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The tumor microenvironment (TME) is a complex structure comprised of tumor, immune and stromal cells, vasculature, and extracellular matrix (ECM). During tumor development, ECM homeostasis is dysregulated. Collagen remodeling by matrix metalloproteinases (MMPs) generates specific collagen fragments, that can be detected in the circulation of cancer patients and correlate with poor disease outcome. Leukocyte-Associated Immunoglobulin-like Receptor-1 (LAIR-1) is an inhibitory collagen receptor expressed on immune cells in the TME and in the circulation. We hypothesized that in addition to ECM collagen, collagen fragments produced in cancer can mediate T cell immunosuppression through LAIR-1. Our analyses of TCGA datasets show that cancer patients with high tumor mRNA expression of MMPs, collagen I and LAIR-1 have worse overall survival. We show that in vitro generated MMP1 or MMP9 collagen I fragments bind to and trigger LAIR-1. Importantly, LAIR-1 triggering by collagen I fragments inhibits CD3 signaling and IFN-γ secretion in a T cell line. LAIR-2 is a soluble homologue of LAIR-1 with higher affinity for collagen and thereby acts as a decoy receptor. Fc fusion proteins of LAIR-2 have potential as cancer immunotherapeutic agents and are currently being tested in clinical trials. We demonstrate that collagen fragment-induced inhibition of T cell function could be reversed by LAIR-2 fusion proteins. Overall, we show that collagen fragments produced in cancer can mediate T cell suppression through LAIR-1, potentially contributing to systemic immune suppression. Blocking the interaction of LAIR-1 with collagen fragments could be an added benefit of LAIR-1-directed immunotherapy.

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Section: Discussionsupporting

confidence: 55%

Section: Discussionmentioning

confidence: 54%

Section: Lair-1 Binding and Signaling By Collagen I Fragments Is Blocked By Lair-2 Fusion Proteinsmentioning

confidence: 66%

Section: Poor Overall Survival Of Cancer Patients With High Mmp Collagen I and Lair-1 Expressionmentioning

confidence: 99%

mentioning

confidence: 96%

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Collagen Fragments Produced in Cancer Mediate T Cell Suppression Through Leukocyte-Associated Immunoglobulin-Like Receptor 1

et al. 2021

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LAIR1 promotes hepatocellular carcinoma cell metastasis and induces M2‐macrophage infiltration through activating AKT‐IKKβ‐p65 axis

Pan,

Shen,

Zhao

et al. 2024

Molecular Carcinogenesis

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LAIR1, a receptor found on immune cells, is capable of binding to collagen and is involved in immune‐related diseases. However, the precise contribution of LAIR1 expressed on hepatocellular carcinoma (HCC) cells to tumor microenvironment is still unclear. In our study, bioinformatics analysis and immunofluorescence were employed to study the correlation between LAIR1 levels and clinical indicators. Transwell and scratch tests were used to evaluate how LAIR1 affected the migration and invasion of HCC cells. The chemotactic capacity and alternative activation of macrophages were investigated using RT‐qPCR, transwell, and immunofluorescence. To investigate the molecular mechanisms, transcriptome sequencing analysis, Western blot, nucleus/cytoplasm fractionation, ELISA, and cytokine microarray were employed. We revealed a significant correlation between the presence of LAIR1 and an unfavorable outcome in HCC. We indicated that LAIR1 promoted migration and invasion of HCC cells through the AKT‐IKKβ‐p65 axis. Additionally, the alternative activation and infiltration of tumor‐associated macrophages induced by LAIR1 were reliant on the upregulation of IL6 and CCL5 within this axis, respectively. In conclusion, blocking LAIR1 was found to be an effective approach in combating the cancerous advancement of HCC.

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Leukocyte-associated immunoglobulin-like receptor-1 blockade in combination with programmed death-ligand 1 targeting therapy mediates increased tumour control in mice

Singh,

Mommers-Elshof,

Vijver

et al. 2024

Cancer Immunol Immunother

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Collagen expression and structure in the tumour microenvironment are associated with tumour development and therapy response. Leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) is a widely expressed inhibitory collagen receptor. LAIR-2 is a soluble homologue of LAIR-1 that competes for collagen binding. Multiple studies in mice implicate blockade of LAIR-1:collagen interaction in cancer as a promising therapeutic strategy. Here, we investigated the role of LAIR-1 in anti-tumour responses. We show that although LAIR-1 inhibits activation, proliferation, and cytokine production of mouse T cells in vitro, tumour outgrowth in LAIR-1-deficient mice did not differ from wild type mice in several in vivo tumour models. Furthermore, treatment with NC410, a LAIR-2-Fc fusion protein, did not result in increased tumour clearance in tested immunocompetent mice, which contrasts with previous data in humanized mouse models. This discrepancy may be explained by our finding that NC410 blocks human LAIR-1:collagen interaction more effectively than mouse LAIR-1:collagen interaction. Despite the lack of therapeutic impact of NC410 monotherapy, mice treated with a combination of NC410 and anti-programmed death-ligand 1 did show reduced tumour burden and increased survival. Using LAIR-1-deficient mice, we showed that this effect seemed to be dependent on the presence of LAIR-1. Taken together, our data demonstrate that the absence of LAIR-1 signalling alone is not sufficient to control tumour growth in multiple immunocompetent mouse models. However, combined targeting of LAIR-1 and PD-L1 results in increased tumour control. Thus, additional targeting of the LAIR-1:collagen pathway with NC410 is a promising approach to treating tumours where conventional immunotherapy is ineffective.

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

Cited by 54 publications

References 68 publications

Collagen Fragments Produced in Cancer Mediate T Cell Suppression Through Leukocyte-Associated Immunoglobulin-Like Receptor 1

Collagen Fragments Produced in Cancer Mediate T Cell Suppression Through Leukocyte-Associated Immunoglobulin-Like Receptor 1

LAIR1 promotes hepatocellular carcinoma cell metastasis and induces M2‐macrophage infiltration through activating AKT‐IKKβ‐p65 axis

Leukocyte-associated immunoglobulin-like receptor-1 blockade in combination with programmed death-ligand 1 targeting therapy mediates increased tumour control in mice

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