Evaluation of anti-cancer potential of a novel RANKL reverse signaling inhibitor

2022 Fiscal Year Final Research Report

• Project/Area Number: 21K19401
• Research Category: Grant-in-Aid for Challenging Research (Exploratory)
• Allocation Type: Multi-year Fund
• Review Section: Medium-sized Section 50:Oncology and related fields
• Research Institution: The University of Tokyo
• Principal Investigator: Honma Masashi 東京大学, 医学部附属病院, 講師 (60401072)
• Project Period (FY): 2021-07-09 – 2023-03-31
• Keywords: RANKL逆シグナル / 癌免疫応答 / シグナル修飾抗体

Outline of Final Research Achievements

We recently found that the RANKL reverse signaling pathway contributes to osteoblast differentiation and bone formation, but the role of RANKL reverse signaling in the immune system remains to be elucidated. In this study, we first found that subcutaneous inoculation of B16-F10 or MC38 cells into RANKL mutant mice, in which RANKL reverse signaling is selectively suppressed, delayed tumor growth compared to wild-type mice. In addition, we obtained modified antibody-like molecules that inhibit RANKL reverse signaling. Administration of the construct inhibiting RANKL reverse signaling to the MC38 subcutaneously-inoculated model suppressed tumor growth as observed in the mutant mice. On the other hand, no additive effect was observed when the antibody-like molecule was used in combination with anti-PD-1 antibody. Further studies will be continued to identify the mechanism of action of inhibiting RANKL reverse signaling.

Free Research Field

癌免疫療法

Academic Significance and Societal Importance of the Research Achievements

近年、PD-1やCTLA-4などの免疫チェックポイント分子に対する中和抗体が、種々の癌種の治療に応用されているが、治療効果には大きな個人差があり、また応答性の低い癌種も残されている。そのため、癌免疫療法の効果を増強できる新規治療法が期待されている。本研究によって、RANKL逆シグナルの抑制が、腫瘍組織の増大を抑制できる事が見出された。今後、その作用メカニズムの詳細を明らかにする事で、新規の薬理作用を有する癌免疫療法の開発に繋がる可能性が期待される。