| Project/Area Number |
19K16705
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| Research Category |
Grant-in-Aid for Early-Career Scientists
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| Allocation Type | Multi-year Fund |
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| Review Section |
Basic Section 50010:Tumor biology-related
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| Research Institution | Tohoku University |
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Principal Investigator |
SU Mei-Tzu 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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| Project Status |
Completed (Fiscal Year 2021)
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| Budget Amount *help |
¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000)
Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2020: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
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| Keywords | MDSC / LILRB4 / gp49B / immunosuppression / metastasis / Immunosuppression / tumor metastasis / miRNA / immune checkpoint / immunotherapy / immune check point |
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| Outline of Research at the Start |
The myeloid-derived suppressor cell (MDSC) plays a critical role in cancer progression. Previous study reported the immunoglobulin-like receptor subfamily B member 4 (LILRB4) expressed on MDSCs correlates with survival in lung cancer patients. Herein, we aim to explore the mechanism of LILRB4 on MDSC-mediated tumor progression. This forefront study could benefit the development of a promising drug for MDSC targeting by blockade of LILRB4, and provide a new strategy for MDSC therapeutic targeting to overcome resistance to Immune checkpoint inhibitors (ICIs).
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| Outline of Final Research Achievements |
Myeloid-derived suppressor cells (MDSCs) are involved in tumor-associated immunosuppression, and dominate tumor progression and metastasis. In this study, we report that the leukocyte immunoglobulin-like receptor subfamily B member 4 (LILRB4, murine ortholog gp49B) orchestrates the polarization of MDSCs to exhibit pro-tumor phenotypes. Gp49B－/－ MDSCs inhibited pro-tumor immune responses such as activation of Treg cells, promotion of cancer cell migration, and stimulation of tumor angiogenesis. Treatment of wild-type tumor-bearing mice with gp49B－/－ M-MDSCs reduced cancer metastasis. Furthermore, gp49B knockout affected plasma exosome composition in terms of increased anti-tumor microRNAs expression. Collectively, our findings reveal that LILRB4/gp49B promotes MDSC-mediated tumor metastasis by regulating the M2-polarization of MDSCs and suppressing the secretion of miR-1 family miRNAs, which facilitate tumor migration and invasion.
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| Academic Significance and Societal Importance of the Research Achievements |
Immune checkpoint inhibitors (ICIs) are used to enhance the antitumor immune response. Several patients do not respond to ICIs due to MDSC-mediated immune escape. Investigation of LILRB4 on how to contribute to MDSC-mediated immunosuppression could provide a new approach for ICI combination therapy.
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