| 研究実績の概要 |
Inhibitory receptors (IRs) such as PD-1 (programmed cell death 1) and CTLA-4 (cytotoxic T lymphocyte-associated antigen 4) play a role in evading anti-tumor responses during tumor progression. Although immunotherapeutic targeting the IRs reinstates dysfunctional anti-tumor immunity via checkpoint blockade, a considerable proportion of cancer patients remain unresponsive to treatment. Herein, we investigate whether the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4), an inhibitory receptor that serves as an immune checkpoint during tumor progression. The results indicated that knockout of gp49B, the ortholog of LILRB4 in murine, reduced tumor metastases in tumor-bearing mice. Additionally, gp49B blockade also inhibited tumor metastases in tumor bearing mice, suggesting LILRB4 (gp49B) acts as an immune checkpoint receptor. Since accumulation of myeloid-derived suppressor cells (MDSCs) in most individuals with cancer suppresses anti-tumor immunity and becomes an obstacle to many immunotherapies, we further demonstrated that the lung-infiltrated MDSCs reduced in gp49B-/- tumor-bearing mice. Moreover, MDSCs from gp49B-/- tumor-bearing mice exhibited a M1-like phenotype with anti-tumor abilities. Knockout of LILRB4 promoted macrophage-secreted anti-tumor cytokines and inhibited migration of tumor cells in vitro. Together, the inhibitory receptor gp49B plays as an immune checkpoint during tumor progression, and blockade of gp49B-triggered inhibitory signals in MDSC should be a therapeutic approach.
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| 現在までの達成度 (区分) |
現在までの達成度 (区分)
2: おおむね順調に進展している
理由
The research goals for the second year are to determine whether LILRB4 influences MDSC infiltration in tumor sites and promotes pro-tumor cytokine secretion to enhance tumor migration. Here, we indeed demonstrated that knockout of LILRB4 suppressed MDSC infiltration in lung tumor tissue, and produced anti-tumor cytokines to inhibit lung cancer cell migration.
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| 今後の研究の推進方策 |
To verify whether LILRB4 indeed serves as an immune checkpoint to regulate tumor progression, the LILRB4-blocking monoclonal antibody will be intraperitoneal injected into tumor-bearing mice, and the tumor metastasis and the percentage of tumor-infiltrated MDSCs will be analyzed.
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