Evaluation of the tumor microimmune environment using mouse models of prostate cancer

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K09570
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Kindai University
• Principal Investigator: De Velasco Marco 近畿大学, 医学部, 講師 (20449838)
• Co-Investigator(Kenkyū-buntansha): 植村 天受 近畿大学, 医学部, 教授 (90213397)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 前立腺癌 / 腫瘍微小環境 / 複合免疫療法 / 遺伝子改変マウスモデル

Outline of Final Research Achievements

Immune checkpoint blockade has transformed the landscape of cancer therapy but has been ineffective in patients with advanced prostate cancer (PCa). The tumor microenvironment (TME) is a major determinant of antitumor immune response. We have used a transgenic mouse of Pten-null PCa to characterize the TME. Our studies showed that myeloid-derived suppressor cells (MDSCs) were associated with PCa progression. Moreover, androgen deprivation therapy further exacerbated MDSC infiltration and was associated with disease progression in castration-resistant tumors. Targeting MDSCs by neoadjuvant blockade of JAK1/2 plus anti-PD-L1 blockade reinvigorated antitumor T cell immune response resulting in improved therapeutic efficacy. Our studies provide additional insights into the role of MDSCs in PCa. Our system provides a robust tool to further develop strategies targeting the immunosuppressive TME of advanced PCa. Our findings were presented in part at the AACR and JCA annual meetings.

Free Research Field

泌尿器腫瘍学

Academic Significance and Societal Importance of the Research Achievements

腫瘍の免疫微小環境変化は免疫チェックポイント阻害治療を開発する上で非常に重要であり、動物実験モデルの有用性は際立っている。我々が開発した前立腺癌マウスモデルは、immunocompetent syngeneicであり、局所の腫瘍内免疫反応のさらなる理解と全身の免疫環境について検証を可能とした。実臨床で使用されている新規抗アンドロゲン薬の治療抵抗に関連する免疫抑制性細胞の同定や新たな免疫チェックポイント阻害薬と分子標的治療薬を組み合わせた併用療法の前臨床試験を本マウスモデルで迅速に検証し、臨床へフィードバックできる意義は大きく、前立腺癌治療への極めて重要なベネフィットとなるであろう。