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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.
Insights
AZD2796, an anti-LILRB2 antibody, reprograms immunosuppressive macrophages to a proinflammatory state. This enhances T cell antitumor responses and reduces tumor growth, offering a promising cancer therapy.
Area of Science:
- Immunology
- Oncology
- Pharmacology
Background:
- Immune checkpoint inhibitors (ICIs) like anti-PD-1 have advanced cancer treatment but face challenges due to immunosuppressive tumor microenvironments (TMEs).
- Tumor-associated macrophages (TAMs) promote TME immunosuppression and inhibit T cell activity.
- Leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2) on TAMs is an inhibitory receptor contributing to immunosuppression.
Purpose of the Study:
- To develop and evaluate AZD2796, a novel anti-LILRB2 antibody designed to counteract TAM-mediated immunosuppression.
- To assess AZD2796's ability to repolarize TAMs towards a proinflammatory phenotype.
- To investigate AZD2796's efficacy as a monotherapy and in combination with anti-PD-1 therapy against solid tumors.
Main Methods:
- Identification of anti-LILRB2 antibodies using single-B-cell encapsulation Immune Replica technology.
- Assessment of AZD2796's impact on macrophage proinflammatory responses in vitro.
- Evaluation of AZD2796's effect on T cell-mediated cytotoxicity in co-culture assays and tumor growth in humanized mouse models.
Main Results:
- AZD2796 successfully shifted macrophage differentiation away from an immunosuppressive phenotype, enhancing their proinflammatory functions.
- AZD2796 significantly boosted T cell antitumor activity when combined with PD-1 blockade.
- Monotherapy with AZD2796 demonstrated a reduction in tumor growth in preclinical humanized mouse models.
Conclusions:
- AZD2796 shows potential as a novel anti-cancer therapeutic by targeting LILRB2-mediated immunosuppression.
- AZD2796 can synergize with existing T cell-based immunotherapies, such as anti-PD-1 antibodies.
- Repolarizing TAMs via LILRB2 blockade represents a viable strategy to enhance antitumor immunity.
