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

SIMPLE SUMMARY: Breast cancer exhibits significant genetic and clinical heterogeneity. Given the importance of understanding tumour-immune interactions to enable the development of novel immunotherapies, identification of novel prognostic biomarkers is important for accurate predictions of the breast cancer patient’s outcome and treatment decisions. The aim of this retrospective study was to assess the potential prognostic value of the leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1), a collagen-binding immunoreceptor tyrosine-based inhibition motifs (ITIM)-bearing inhibitory receptor, that plays an important role in the regulation of the immune system and tumour progression. Our study highlights the importance of LAIR-1 expression and the role of the immune microenvironment in breast cancer progression and worse clinical outcome. Further functional investigation warrants understanding the crosstalk between immune checkpoint blocking agents, immune microenvironment and its underlying mechanisms for targeted therapy development. ABSTRACT: Background: The leukocyte-associated immunoglobulin-like receptor-1 (LAIR-1) plays a role in immune response homeostasis, extracellular matrix remodelling and it is overexpressed in many high-grade cancers. This study aimed to elucidate the biological and prognostic role of LAIR-1 in invasive breast cancer (BC). Methods: The biological and prognostic effect of LAIR-1 was evaluated at the mRNA and protein levels using well-characterised multiple BC cohorts. Related signalling pathways were evaluated using in silico differential gene expression and siRNA knockdown were used for functional analyses. Results: High LAIR-1 expression either in mRNA or protein levels were associated with high tumour grade, poor Nottingham Prognostic Index, hormone receptor negativity, immune cell infiltrates and extracellular matrix remodelling elements. High LAIR-1 protein expression was an independent predictor of shorter BC-specific survival and distant metastasis-free survival in the entire BC cohort and human epidermal growth factor receptor 2 (HER2)+ subtype. Pathway analysis highlights LAIR-1 association with extracellular matrix remodelling-receptor interaction, and cellular proliferation. Depletion of LAIR-1 using siRNA significantly reduced cell proliferation and invasion capability in HER2+ BC cell lines. Conclusion: High expression of LAIR-1 is associated with poor clinical outcome in BC. Association with immune cells and immune checkpoint markers warrant further studies to assess the underlying mechanistic roles.