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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 shows 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. [ABSTRACT FROM AUTHOR]

Despite major successes with inhibitory receptor blockade in cancer, the identification of novel inhibitory receptors as putative drug targets is needed due to lack of durable responses, therapy resistance, and side effects. Most inhibitory receptors signal via immunoreceptor tyrosine-based inhibitory motifs (ITIMs) and previous studies estimated that our genome contains over 1600 ITIM-bearing transmembrane proteins. However, testing and development of these candidates requires increased understanding of their expression patterns and likelihood to function as inhibitory receptor. Therefore, we designed a novel bioinformatics pipeline integrating machine learning-guided structural predictions and sequence-based likelihood models to identify putative inhibitory receptors. Using transcriptomics data of immune cells, we determined the expression of these novel inhibitory receptors, and classified them into previously proposed functional categories. Known and putative inhibitory receptors were expressed across different immune cell subsets with cell type-specific expression patterns. Furthermore, putative immune inhibitory receptors were differentially expressed in subsets of tumour infiltrating T cells. In conclusion, we present an inhibitory receptor pipeline that identifies 51 known and 390 novel human inhibitory receptors. This pipeline will support future drug target selection across diseases where therapeutic targeting of immune inhibitory receptors is warranted., Competing Interests: AS AS is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, AM AMB is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, Hv HJR is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, SV, RK, AY No competing interests declared, Mv MV is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, JK JK is cofounder, shareholder and scientific advisor of GADETA. JK is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, CK CK is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, MP IR is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, LM LM has received funding for investigator-initiated studies on inhibitory receptors from Boehringer Ingelheim, NextCure, NGM Biopharmaceuticals and Argenx. LM is named as co-inventor on a patent application (patent application number: PCT/NL2024/050501) based on this work, (© 2024, Singh et al.)