Clarification of immune status in urological cancer tissues and identification for novel therapeutic targets

• Project/Area Number: 17K16790
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Urology
• Research Institution: Osaka University
• Principal Investigator: Kawashima Atsunari 大阪大学, 医学系研究科, 助教 (50746568)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥2,730,000 (Direct Cost: ¥2,100,000、Indirect Cost: ¥630,000)
• Keywords: 腎細胞癌 / 尿路上皮癌 / PD-1 / TIM-3 / ニボルマブ / 効果予測 / 予後予測 / 腫瘍悪性度 / Tim-3 / 疲弊化T細胞 / 泌尿器科癌 / 癌免疫 / 新規治療標的

Outline of Final Research Achievements

We examined the expression pattern of infiltrating T lymphocytes (TILs) in cancer tissues in renal cell carcinoma and urothelial carcinoma and revealed that expression pattern significantly correlated with tumor malignancy.
In addition, TILs are fractionated based on the expression pattern of PD-1 and TIM-3 of both CD4 and CD8 T cells to evaluate their functions. We found that fraction of exhausted CD8 T cells and regulatory CD4 T cells were elevated and the multi-functionality of CD4 T cells was decreased. Moreover, the prognosis of patients with high grade tumor treated by anti PD-1 antibody was poor. From the above, 1)reactivation of CD8 T cells, 2)removal of regulatory T cells from the tumor environment and 3)recovery of multi-functionality of CD4 T cell are necessary for the refractory case against the current anti-PD-1 antibody single agent.

Academic Significance and Societal Importance of the Research Achievements

抗PD-1抗体をはじめとするイムノチェックポイント分子を標的とした癌免疫療法は有望な治療であるものの、その効果は限定的である。当研究では、ヒト組織から抽出した癌組織内リンパ球の機能を評価し、腫瘍の悪性度と癌組織内リンパ球の機能が相関すること、また腫瘍の悪性度が抗PD-1抗体の治療効果と有意に相関することを明らかにした。これは、現在存在していない、腎細胞癌に対する抗PD-1抗体治療の効果予測因子として重要な意味を持つと考えている。

Research Products

• [Journal Article] Phenotypic Analysis of Tumor Tissue?Infiltrating Lymphocytes in Tumor Microenvironment of Bladder Cancer and Upper Urinary Tract Carcinoma (2019)
  • Author(s): Kawashima Atsunari、Kanazawa Takayuki、Jingushi Kentaro、Kato Taigo、Ujike Takeshi、Nagahara Akira、Fujita Kazutoshi、Morimoto-Okazawa Akiko、Iwahori Kota、Uemura Motohide、Imamura Ryoichi、Wada Hisashi、Nonomura Norio
  • Journal Title: Clinical Genitourinary Cancer Volume: 17 Issue: 2 Pages: 114-124
  • DOI: 10.1016/j.clgc.2018.11.004
  • Peer Reviewed
• [Presentation] The significance as a prognostic predictor of immunological phenotype in urothelial carcinoma varies depending on the tumor sites (2018)
  • Author(s): Atsunari Kawashima
  • Organizer: Asia Urological Association
  • Int'l Joint Research
• [Presentation] Overall dysfunction of T cells was significantly correlated with tumor grade in Renal Cell Carcinoma patients (2018)
  • Author(s): Atsunari Kawashima
  • Organizer: 35th Korea-Japan Urological Congress
  • Int'l Joint Research
• [Presentation] 膀胱癌と上部尿路上皮癌における癌局所内免疫状態の比較 (2018)
  • Author(s): 河嶋厚成
  • Organizer: 第77回日本癌学会総会
• [Presentation] 腎細胞癌の腫瘍悪性度は癌組織内T細胞の機能低下と有意な相関示す (2018)
  • Author(s): 河嶋厚成
  • Organizer: 第68回日本泌尿器科学会中部総会