The ITIM-Containing Receptor: Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) Modulates Immune Response and Confers Poor Prognosis in Invasive Breast Carcinoma

Joseph, Chitra; Alsaleem, Mansour; Toss, Michael S.; Kariri, Yousif; Althobiti, Maryam; Alsaeed, Sami; Aljohani, Abrar; Narasimha, Pavan L.; Mongan, Nigel P.; Green, Andrew; Rakha, Emad A.

doi:10.3390/cancers13010080

Cited by 16 publications

(12 citation statements)

References 62 publications

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“…One such study, for example, has shown that reducing tumor stiffness and collagen organization via inhibition of the collagen-crosslinking enzyme lysyl oxidase (LOX) increased T cell migration, tumor infiltration with CD8 + T cells, and antitumor activity of PD-1 blockade therapy in a model of murine pancreatic cancer ( 32 ). In addition to providing a physical obstacle to immune cells, collagens can also bind to the inhibitory receptor LAIR-1, which is expressed across multiple immune cell subsets ( 33 ) and correlates with poor prognosis in several tumor types ( 34 , 35 ). LAIR-1 signaling has been shown in preclinical models to drive T cell suppression and a TIM-3 + exhausted T cell phenotype that mediates resistance to ICB ( 9 ).…”

Section: Discussionmentioning

confidence: 99%

Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication

Horn¹,

Chariou²,

Gameiro³

et al. 2022

Journal of Clinical Investigation

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Collagens in the extracellular matrix (ECM) provide a physical barrier to tumor immune infiltration, while also acting as a ligand for immune inhibitory receptors. Transforming growth factor-β (TGF-β) is a key contributor to shaping the ECM by stimulating the production and remodeling of collagens. TGF-β-activation signatures and collagen-rich environments have both been associated with T-cell exclusion and lack of responses to immunotherapy. Here we describe the effect of targeting collagens that signal through the inhibitory leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) in combination with blockade of TGF-β and programmed cell death ligand 1 (PD-L1). This approach remodeled the tumor collagenous matrix, enhanced tumor infiltration and activation of CD8 + T cells, and repolarized suppressive macrophage populations resulting in high cure rates and long-term tumor-specific protection across murine models of colon and mammary carcinoma. The results highlight the advantage of direct targeting of ECM components in combination with immune checkpoint blockade therapy.

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Section: Discussionmentioning

confidence: 99%

Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication

Horn¹,

Chariou²,

Gameiro³

et al. 2022

Journal of Clinical Investigation

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“…Joseph et al showed that LAIR-1 highly expressed at mRNA and protein levels was a signi cant factor in breast cancer-speci c survival (BCSS) and distant metastasis-free independent predictors of poor survival for distant metastasis-free survival (DMFS), unaffected by other complicating prognostic elements including tumor size, tumor grade, stage, CD3+, CD8+, HER2+ status, and chemotherapy (Joseph et al, 2020). Peng et al showed that LAIR-1 is a potential marker of ICIs in lung cancer (Peng et al, 2020).…”

Section: Discussionmentioning

confidence: 99%

Regulatory Effects and Mechanism of Immune Inhibitory Receptor LAIR-1 in Non-small Cell Lung Cancer

Liú

et al. 2023

Preprint

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Purpose To investigate the association of leukocyte-associated immunoglobulin-like receptor 1 (LAIR-1) levels with clinicopathological features and prognosis of non-small cell lung cancer (NSCLC). Methods The expression of LAIR-1 and clinicopathological data were downloaded from The Cancer Genome Atlas database and Gene Expression Omnibus for analyzing the correlation between LAIR-1 expression and prognosis. Tissue samples from 118 NSCLC patients and 47 paired adjacent cancer tissues were collected and the expression of LAIR-1 in NSCLC tissues was detected by immunohistochemistry. The statistical analysis was performed for association analysis of LAIR-1 expression and clinicopathological properties. Lentiviral transfection of NSCLC cell lines A549 and SK-MES-1 for overexpressing LAIR-1 were used to evaluate the role of LAIR-1 in regulating cell cycle and apoptosis in NSCLC cell lines by flow cytometry. Results LAIR-1 expression was lower in NSCLC tissues than in para-cancerous tumor tissues, and overall survival time was lower in the LAIR-1 low- expression group. Univariate analysis revealed that the low expression of LAIR-1 was related to lymph node metastasis, tumor stage, etc. in NSCLC patients. The LAIR-1 low-expression group of the NSCLC patients showed higher mortality, tumor progression, and lower overall survival and disease-free survival. Multivariate analyses demonstrated that the expression of LAIR-1 in squamous carcinoma patients had a negative correlation with NSCLC progression. In vitro experiments showed that the overexpression of LAIR-1 blocked the squamous cell carcinoma at the G1 stage and promoted cell apoptosis. Conclusion LAIR-1 was closely associated with lymph node metastasis, tumor stage, and patients’ prognosis.

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“…Four different types of ligands are described, including components of the complement system and collagens, suggesting a potential immune-regulatory function of the extracellular matrix ( 175 , 176 ). In a retrospective study, LAIR1 expression was found to associate to poor prognosis in invasive breast carcinoma ( 177 ), but also to resistance to PD1/PD-L1 inhibition in patients ( 178 ). Of interest, LAIR1 blockade by antagonist antibodies inhibited tumor development in a humanized mouse model by affecting, among others, the recruitment of pro-tumorigenic pDCs ( 179 ).…”

Section: Irs Expressed By Pdcs and Their Role In Physiology And Tumorsmentioning

confidence: 99%

Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer

Tiberio,

Laffranchi,

Zucchi

et al. 2024

Front. Immunol.

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Plasmacytoid dendritic cells (pDCs) are the major producers of type I interferons (IFNs), which are essential to mount antiviral and antitumoral immune responses. To avoid exaggerated levels of type I IFNs, which pave the way to immune dysregulation and autoimmunity, pDC activation is strictly regulated by a variety of inhibitory receptors (IRs). In tumors, pDCs display an exhausted phenotype and correlate with an unfavorable prognosis, which largely depends on the accumulation of immunosuppressive cytokines and oncometabolites. This review explores the hypothesis that tumor microenvironment may reduce the release of type I IFNs also by a more pDC-specific mechanism, namely the engagement of IRs. Literature shows that many cancer types express de novo, or overexpress, IR ligands (such as BST2, PCNA, CAECAM-1 and modified surface carbohydrates) which often represent a strong predictor of poor outcome and metastasis. In line with this, tumor cells expressing ligands engaging IRs such as BDCA-2, ILT7, TIM3 and CD44 block pDC activation, while this blocking is prevented when IR engagement or signaling is inhibited. Based on this evidence, we propose that the regulation of IFN secretion by IRs may be regarded as an “innate checkpoint”, reminiscent of the function of “classical” adaptive immune checkpoints, like PD1 expressed in CD8+ T cells, which restrain autoimmunity and immunopathology but favor chronic infections and tumors. However, we also point out that further work is needed to fully unravel the biology of tumor-associated pDCs, the neat contribution of pDC exhaustion in tumor growth following the engagement of IRs, especially those expressed also by other leukocytes, and their therapeutic potential as targets of combined immune checkpoint blockade in cancer immunotherapy.

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The ITIM-Containing Receptor: Leukocyte-Associated Immunoglobulin-Like Receptor-1 (LAIR-1) Modulates Immune Response and Confers Poor Prognosis in Invasive Breast Carcinoma

Cited by 16 publications

References 62 publications

Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication

Remodeling the tumor microenvironment via blockade of LAIR-1 and TGF-β signaling enables PD-L1–mediated tumor eradication

Regulatory Effects and Mechanism of Immune Inhibitory Receptor LAIR-1 in Non-small Cell Lung Cancer

Inhibitory receptors of plasmacytoid dendritic cells as possible targets for checkpoint blockade in cancer

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