Identification of novel immune checkpoint molecule in glioma, lair1

Abstract BACKGROUND In recent years, emerging evidence indicates that tumor-associated myeloid cells (TAMCs) affect cancer progression. But the molecular mechanisms and signaling pathways involved in the TAMCs’ interaction with extracellular matrix (ECM) and tumor stroma are incompletely understood. Checkpoint inhibition therapy targets immune inhibitory receptors, such as CTLA-4 and PD-1, which have become a major weapon in fighting cancer. These antibodies demonstrate apparent advantages such as being easy to use, broad applicability, and durable clinical response. Leukocyte-Associated Immunoglobulin-like Receptor 1 (LAIR1), also called CD305, a collagen-binding immunoreceptor tyrosine-based inhibition motifs (ITIM)-bearing inhibitory receptor, was identified to present on almost all immune cell populations and overexpressed in cancers of human patients. However, LAIR1’s role and regulation in solid cancers are poorly defined. OBJECTIVE To identify LAIR1 as a new class of immune checkpoints in cancers that impacts TAMCs-associated tumor immunity. Further functional investigation warrants understanding the crosstalk between LAIR1-related immune checkpoint blocking agent(s), immune micro-environment, and its underlying mechanisms for targeted therapy development. METHODS Murine GBM cell line KR158-Luciferase cell line was used to set up the mouse model. Tumor-bearing mice were administered the Anti-LAIR1 blockade and IgG, followed by IVIS imaging for tumor growth and survival were recorded. The presentation and phenotype of immune cell populations in tumors and spleens were measured through scRNA-Seq. RESULTS GBM is one of these tumors that overexpress LAIR1 based on the TCGA analysis. LAIR1 molecules express highly on macrophages, monocytes, DCs, and activated T cells, not on the naive T cells. We found that LAIR1 blockade enhanced survival in preclinical GBM models. LAIR1 blockade reduced the presentation and function of TAMCs in tumors. What's more, LAIR1 blockade provided a synergetic antitumor effect with CD70 CAR T cells. CONCLUSION This study suggests that we identified a novel immune checkpoint molecule, LAIR1, which can limit tumor progression.