LILRB4 suppresses immunity in solid tumors and is a potential target for immunotherapy

Immune receptors expressed on TAMs are intriguing targets for tumor immunotherapy. In this study, we found inhibitory receptor LILRB4 on a variety of intratumoral cell types in murine tumor models and human cancers; most prominently on TAMs. LILRB4, known as gp49B in mice, is a LILRB family receptor. Human and murine LILRB4 have 2 extracellular domains but differ in number of intracellular ITIM motifs (3 vs 2). We observed high correlation in LILRB4 expression with other immune inhibitory receptors. After tumor challenge, LILRB4-/- mice and mice treated with anti-LILRB4 antibody showed reduced tumor burden and increased survival. LILRB4-/- genotype or LILRB4 blockade increased tumor immune-infiltrates and CD8+ T cells to Treg ratio and modulated phenotypes of TAMs toward less suppressive, CD4+ T cells to Th1 effector, and CD8+ T cells to less exhausted. These findings reveal that LILRB4 strongly suppresses tumor immunity in TME and that alleviating that suppression provides anti-tumor efficacy.