Identification of unique antigens by next generation sequencing and development of individualized cancer immunotherapy in clear cell renal cell carcinoma

2015 Fiscal Year Final Research Report

• Project/Area Number: 25430148
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Tumor therapeutics
• Research Institution: The University of Tokyo
• Principal Investigator: Matsushita Hirokazu 東京大学, 医学部附属病院, 講師 (80597782)
• Co-Investigator(Kenkyū-buntansha): KAKIMI Kazuhiro 東京大学, 医学部附属病院, 特任教授 (80273358) ; KUME Haruki 東京大学, 医学部附属病院, 登録研究員 (10272577)
• Project Period (FY): 2013-04-01 – 2016-03-31
• Keywords: 腎がん / 次世代シーケンス / 遺伝子変異 / MHCクラスI結合予測法 / 免疫チェックポイント分子 / ネオアンチゲン / 個別化がん免疫治療

Outline of Final Research Achievements

We established a method to identify neoantigens derived from tumor-specific mutations by combining next generation sequencing (NGS) with MHC class I binding algorism. In 97 clear cell renal cell carcinoma (ccRCC), we demonstrated that patients with high neoantigen load and HLA expression correlated with better clinical outcomes and also they expressed high CD8A, perforin and granzyme A. However, immunosuppressive molecules such as CTLA-4 and PD-1 were also highly expressed in the tumor, suggesting that abundant neoepitopes associated with greater antitumor effector immune responses were counterbalanced by a strongly immunosuppressive microenvironment. We have created the system predicting candidate neoantigens and showed that neoantigen load, antigen presentation machinery, and immune signatures determine prognosis in ccRCC. They are prerequisites for individualized cancer immunotherapy development in the patients.

Free Research Field

腫瘍治療学