LILRB4 specific overexpression in myeloid cells promotes tumor progression and immunosuppression in mouse models

Leukocyte immunoglobulin like receptor B4 (LILRB4) was considered to promote tumor progression and immunosuppression in various malignancies. As a murine homolog of LILRB4, gp49B has been employed in numerous mouse models to investigate the immunosuppressive properties of LILRB4. However, gp49B differs significantly from LILRB4 in its amino acid sequence and intracellular domains. In this study, we developed a conditional mouse model that overexpresses LILRB4 specifically in myeloid cells to investigate its effects on solid tumors and hematological malignancies. Our results showed that the physiological structure and overall immune system of LILRB4^L/L; Cre mice were normal. LL2 tumors in LILRB4^L/L; Cre mice exhibited increased size and weight, with elevated levels of immunosuppressive markers programmed cell death protein 1 (PD-1) and T cell immunoglobulin and mucin-domain containing-3 (TIM-3) on infiltrating CD3⁺ T cells, alongside a shift in tumor-associated macrophages (TAMs) from M1-type to M2-type. In the C1498 model, LILRB4 overexpression promoted tumor progression and metastasis, evidenced by increased bioluminescence and enhanced infiltration of monocytic myeloid-derived suppressor cells (M-MDSCs). Real-time PCR analysis showed upregulation of immunosuppressive mRNAs, including colony-stimulating factor 1 (CSF1), arginase1 (Arg1), macrophage galactose N-acetyl-galactosamine specific lectin 2 (Mgl2) and interleukin-1β (IL-1β) while downregulating pro-inflammatory markers like nitric oxide synthase 2 (Nos2). These findings indicate that LILRB4 fosters an immunosuppressive microenvironment that supports tumor progression. LILRB4^L/L; Cre mice may serve as a promising tool for studying targeted LILRB4 tumor immunotherapy.