Strategy to overcome the refractoriness of hematological malignancies through inhibition of intracellular signaling and immune enhancement

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K08726
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 54010:Hematology and medical oncology-related
• Research Institution: Dokkyo Medical University (2021-2022); The University of Tokyo (2020)
• Principal Investigator: Imai Yoichi 獨協医科大学, 医学部, 教授 (10345209)
• Co-Investigator(Kenkyū-buntansha): 安井 寛 聖マリアンナ医科大学, 医学部, 准教授 (40448593)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: AML / TIGIT / CD155/CD112 / MM / HDAC inhibitor / Akt inhibitor

Outline of Final Research Achievements

Acute myeloid leukemia (AML) relapse is related to escape from antitumor immunity. Binding of TIGIT on natural killer (NK) and T cells to CD155/CD112 in tumors is supposed to be inhibitory for antitumor immunity. CD155 and CD112 expression was specifically downregulated by FLT3 inhibition in FLT3-mutated cell lines. Direct cytotoxicity and antibody-dependent cellular cytotoxicity (ADCC) against these cells by NK cells were enhanced.
In addition, the HDAC inhibitor suppressed the growth of drug-resistant multiple myeloma (MM) cell lines and enhanced ADCC of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation and were supposed to overcome resistance to lenalidomide.

Free Research Field

血液内科学

Academic Significance and Societal Importance of the Research Achievements

AMLやMMなどの造血器腫瘍は新規治療法が開発されているが、再発も多く難治性の疾患である。AMLの治療抵抗性獲得には抗腫瘍免疫からの回避が重要である。本研究では、AMLに対する分子標的治療薬FLT3阻害剤が細胞内シグナル異常に加えて、NK細胞による抗腫瘍免疫を強化して高い治療効果が期待されることを明らかにした。MMに対しても、HDAC阻害剤とAkt阻害剤の併用は細胞内シグナル阻害と免疫賦活化を介して治療抵抗性を克服することが示された。本研究で得られた知見は、造血器腫瘍治療における細胞内シグナル修飾と免疫賦活化の両面からの難治性の克服を目指した新たな治療法開発の基盤を形成することが期待される。