Investigation of Biomarkers to Predict the Efficacy of Immune Checkpoint Inhibitor Therapy in Renal Cell Carcinoma

2023 Fiscal Year Final Research Report

• Project/Area Number: 21K16750
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 56030:Urology-related
• Research Institution: Akita University
• Principal Investigator: Kashima Soki 秋田大学, 医学系研究科, 助教 (50842952)
• Project Period (FY): 2021-04-01 – 2024-03-31
• Keywords: 腎細胞癌 / 免疫チェックポイント阻害薬 / 腫瘍微小環境 / バイオマーカー / CD8 T細胞 / 制御性T細胞 / 腫瘍免疫 / 抗PD1抗体

Outline of Final Research Achievements

Numerous studies of other solid tumors have investigated predictive biomarkers for ICI response, including tumor mutation burden (TMB) and the presence of microsatellite instability due to defects in DNA mismatch repair genes. While these biomarkers have predictive value in high TMB tumors, they are not associated with ICI efficacy in patients with modest TMB tumors like renal cell carcinoma (RCC). To address these challenges and uncover biomarkers of therapeutic response to ICIs in RCC, we analyzed the tumor microenvironment in treatment-naive tissue, and paired peripheral blood both pre- and post-ICI treatment. We found that exhausted CD8 T cells showed significant changes in responders (R) versus non-responders (NR), effector cytokines were significantly upregulated in the plasma of R, and Foxp3+ cells were significantly more frequent in pre-treatment specimens of NR. We identified specific molecules and subclusters that could potentially predict the efficacy of ICI therapy in RCC.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

腎癌において、継時的な末梢血単核球細胞の表現型解析・血漿中のマルチプレックスタンパク解析・tissue microarrayによる免疫染色解析を同一患者由来のサンプルで網羅的に行った報告は過去に無く、本研究が初の試みである。我々はこの多面的アプローチにより、腎癌におけるICI治療効果を予測しうる早期バイオマーカーとして新規分子および細胞群を同定した。今後は本研究で同定したバイオマーカーを用いて前向きな検討で早期に免疫チェックポイント阻害薬の治療効果が予測できるかどうか評価することで、現状における腎癌のICI治療効果予測の課題を解決できる可能性を秘めている。