2020 Fiscal Year Research-status Report
The role of LILRB4 on MDSC-mediated immunosuppression in tumor environment
| Project/Area Number |
19K16705
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| Research Institution | Tohoku University |
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Principal Investigator |
蘇 美慈 東北大学, 加齢医学研究所, 助教 (00812116)
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| Project Period (FY) |
2019-04-01 – 2022-03-31
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| Keywords | immune checkpoint / MDSC / tumor metastasis / immunotherapy / immunosuppression / LILRB4 / gp49B |
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| Outline of Annual Research Achievements |
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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| Current Status of Research Progress |
Current Status of Research Progress
2: Research has progressed on the whole more than it was originally planned.
Reason
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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| Strategy for Future Research Activity |
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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| Causes of Carryover |
Due to the outbreak of COVID-19, I did not attend the meeting this fiscal year. Surplus expenditure will be the article cost in next fiscal year.
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