Immunomodulatory effects of HDAC inhibitors for combination immunotherapy in prostate cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K18104
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Kindai University
• Principal Investigator: Banno Eri 近畿大学, 医学部, 助教 (60580793)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 前立腺癌 / HDAC阻害剤 / 複合免疫療法 / 腫瘍免疫微小環境 / TP53変異

Outline of Final Research Achievements

In prostate cancer cell lines, there was no significant difference in sensitivity to HDAC inhibitors (vorinostat, entinostat) depending on Tp53 mutation. In mouse models of prostate cancer, a HDAC inhibitor vorinostat showed the antitumor effect, downregulating expression of genes associated with tumor-associated macrophages, regulatory T cells, and bone marrow-derived suppressor cells, while downregulating expression of genes associated with anti-tumor cytotoxic CD8+ cells. No significant difference was observed in the number of tumor-infiltrating CD8+ T cells and regulatory T cells between the combination therapy (HDAC inhibitor and anti-PD-1 antibody) and the monotherapy of anti-PD-1 antibody.

Free Research Field

泌尿器腫瘍学

Academic Significance and Societal Importance of the Research Achievements

免疫チェックポイント阻害薬の登場により、がん免疫療法の有用性が認識されている。前立腺癌におけるHDAC阻害剤の抗腫瘍効果と免疫調節機能への作用は明らかになったが、抗PD-1抗体と併用する複合免疫療法しての効果は限局的であった。本研究をもとに、前立腺癌に対するHDAC阻害剤以外の複合免疫療法の可能性を期待する。また、前立腺癌ではTP53変異が高頻度に認められ、引き続きTP53をターゲットにした治療に繋がる研究も望まれる。