Related Experiment Video
Updated: May 11, 2025
Functional Characterization of Regulatory Macrophages That Inhibit Graft-reactive Immunity
Published on: June 7, 2017
LILRB2 blockade facilitates macrophage repolarization and enhances T cell-mediated antitumor immunity
Des C Jones1,2, Lorraine Irving3, Rebecca Dudley4
1ICC, Early Oncology R&D, AstraZeneca, Cambridge, UK desjones@hotmail.com.
Background:
Immune checkpoint inhibitors have revolutionized the treatment of solid tumors, enhancing clinical outcomes by releasing T cells from inhibitory effects of receptors like programmed cell death protein 1 (PD-1). Despite these advancements, achieving durable antitumor responses remains challenging, often due to additional immunosuppressive mechanisms within the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) contribute significantly to the immunosuppressive TME and play a pivotal role in shaping T cell-mediated antitumor responses. Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2), expressed on myeloid cells, including TAMs, is an inhibitory receptor, which contributes to macrophage-mediated immunosuppression. In this study, we present AZD2796, a high-affinity anti-LILRB2 antibody designed to repolarize TAMs from an immunosuppressive to a proinflammatory phenotype.
Methods:
Anti-LILRB2 antibodies were identified using single-B-cell encapsulation Immune Replica technology. The ability of AZD2796 to enhance proinflammatory responses from macrophages treated with CD40 ligand or lipopolysaccharide was assessed using a macrophage stimulation assay. A tumor cell/macrophage/T cell co-culture assay was developed to evaluate the effect of AZD2796, as a single agent and in combination with an anti-PD-1 antibody, on the cytolytic activity of antigen-specific T cells. In vivo assessments were then carried out to determine the ability of AZD2796 to alter tumor growth rate in mice humanized with CD34 hematopoietic stem cells.
Results:
In preclinical assessments, AZD2796 skewed macrophage differentiation away from an immunosuppressive phenotype and enhanced the proinflammatory function of macrophages. AZD2796 significantly increased the anti-tumor response of T cells following PD-1 checkpoint blockade, while AZD2796 monotherapy reduced tumor growth in humanized mouse models.
Conclusions:
These findings support the potential of AZD2796 as an anti-cancer therapy, with the ability to synergize with T-cell-based therapeutics.
