| Project/Area Number |
21K15466
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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 49070:Immunology-related
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| Research Institution | Kyoto University |
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Principal Investigator |
徐 彦 京都大学, 医学研究科, 特定助教 (00896631)
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| Project Period (FY) |
2021-04-01 – 2024-03-31
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| Project Status |
Granted (Fiscal Year 2021)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2023: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2022: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2021: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
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| Keywords | mesenchymal stroma cells / Sipa1 / T cell infiltration / MSCs / Tumor microenvironment / Cancer immunotherapy |
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| Outline of Research at the Start |
Mice deficient of Sipa1, which encodes Rap1 GTPase-activating protein, showed significantly increased resistance to different cancer cells with increased host stromal reactions. While Sipa1 deficiency uncovered a host immune mechanism potentially capable of eradicating cancer cells via coordinated interplay between mesenchymal stromal cells (MSCs) and immune T cells, the detail mechanism has not been demonstrated. This research is to clarify the biological significance of stromal reactions in cancer tissue microenvironment and to develop a new therapeutic strategy for cancer immunotherapy.
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| Outline of Annual Research Achievements |
1. Three distinct subsets of tumor mesenchymal stroma cells (MSCs) were identified. They had different functions in tumor tissues and their comparable phenotypes could be barely detectable in normal tissues. In the tumor tissues of Sipa1 deficient host, the proliferation and differentiation of reticular fibroblastic like tumor MSCs (FB/FC subtype) were activated, but myofibrobrastic like MSCs (FA subtype) were not be affected.
2. Tumor tissues of Sipa1 deficient host showed a remarkably elevated expression of selected T cell-chemokines in association with a significant increase in T cell infiltration. Tumor MSCs of Sipa1 deficient host also showed an increased expression of selected chemokine genes. qPCR analysis confirmed that the tumor-associated MSCs of Sipa1 deficient host show a markedly increased expression of T cell-chemokine genes (Cxcl9, 10), and this was associated with the increased T cell infiltration in tumor tissues. Immunostaining analysis also reveals strong expression of Cxcl9 in the reticular MSCs surrounding tumor cells of KO hosts, which was associated with a significant accumulation of T cells.
3. In Sipa1 deficient tumor MSCs IFN gama-signaling pathway was enhanced. It may underlie the remarkably augmented T-cell chemokine gene expression in Sipa1 deficient MSCs in tumor tissues.
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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
Identified the tumor MSCs subtypes by FACS and immunostaining analysis as planed, and performed the gene expression analysis in MSCs. Clarified MSCs in tumor tissues of Sipa1 deficient host showed a remarkably elevated expression of selected T cell-chemokines in association with a marked increase in T cell infiltration.
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| Strategy for Future Research Activity |
Clarify factors and signal pathways inducing such functional diversification of tumor MSCs in the anti-tumor mechanism. Advanced gene and protein expression analysis of MSC subtypes will be performed to clarify their anti tumor affection, especially the local T cell response-inducing effect.
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