Elucidation of molecular mechanisms involved in the regulation of tumor immunity in osteosarcoma

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K07134
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Hoshi University
• Principal Investigator: Shimizu Takatsune 星薬科大学, 薬学部, 准教授 (40407101)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 骨肉腫 / 腫瘍免疫 / がん微小環境 / 転移巣

Outline of Final Research Achievements

Immunotherapy is not effective for osteosarcoma (OS), and elucidation of its molecular mechanisms is necessary to overcome refractory cases. Using our unique OS model and dropout screening, candidate molecules that are important for OS cells to evade the immune attack have been extracted. OS cells with modified expression of the candidate molecules were inoculated into C57BL/6 wild type and SCID mice to identify the molecules that were specifically involved in the decreased tumorigenicity in wild-type mice. The results indicated that p53-related molecules and an actin-binding protein might inhibit tumor immunity. Moreover, knockout of mutant p53 in OS cells decreased the primary lesion. However, primary and metastatic lesions still developed even with the reduced expression level of these molecules. Therefore, it is necessary to further narrow down of the promising candidate molecules and elucidate the molecular mechanisms related to the exhaustion of the tumor immunity.

Free Research Field

腫瘍生物学

Academic Significance and Societal Importance of the Research Achievements

骨肉腫は免疫療法が奏効せず、その分子機構解明は、難治症例に対する有効な治療法開発に繋がる。本研究を通じて、腫瘍免疫回避に関わる骨肉腫側の分子（p53関連分子とアクチン結合タンパク）が明らかとなった。これらの分子は高発現により、腫瘍内のT細胞の減少と疲弊をもたらす可能性がある。さらなる検証を要するが、これらの結果は骨肉腫への効果的な腫瘍免疫療法確立に貢献すると考えられる。また、研究から派生し、変異型p53の骨肉腫病態における役割と転写制御に関する分子機構が解明された。さらに、nintedanibが新たな治療手段として使用できる可能性が示され、骨肉腫の新規治療法開発に貢献する可能性がある。