Exploration of novel molecular targeted therapies based on tumor microenvironmental profile in endometrial cancer

• Project/Area Number: 17K16829
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: University of Tsukuba
• Principal Investigator: Shikama Ayumi 筑波大学, 医学医療系, 講師 (40778627)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2019: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2018: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2017: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000)
• Keywords: 子宮内膜癌 / 腫瘍微小環境 / 免疫チェックポイント機構 / 癌

Outline of Final Research Achievements

The aim of our study was to investigate the precise prognostic significance of the Tumor microenvironment (TME) profile in endometrial carcinoma. We performed immunohistochemistry of the TME proteins, PD-L1, PD-1, CD4, CD8, CD68, and VEGF in endometrial carcinomas from 221 patients. High PD-L1 in tumor cells (TCs) was associated with better OS, whereas high PD-L1 in tumor-infiltrating immune cells (TICs) was associated with worse OS. Univariate and multivariate analyses of prognostic factors revealed that high PD-L1 in TCs and high density of CD4+ TICs were significant and independent for favorable OS. The current findings indicate that PD-L1 and CD4+ helper T cells may be reasonable targets for improving survival through manipulating chemosensitivity, providing significant implications for combining immunotherapies into the therapeutic strategy for endometrial carcinoma.

Academic Significance and Societal Importance of the Research Achievements

子宮内膜癌における腫瘍微小環境と予後との関連性の調査結果より、PD-L1とCD4陽性ヘルパーT細胞が化学療法感受性に関与すること、PD/PD-L1を介した免疫チェックポイント機構が、子宮内膜癌での腫瘍微小環境を調節することにより。予後を改善する可能性があることが示唆された。このことは、選択肢の少ない子宮内膜癌の治療戦略において、免疫チェックポイント阻害剤を組み合わせる治療の可能性を拡大する上で重要な知見となったと考えられる。

Research Products

• [Journal Article] PD-L1 and CD4 are independent prognostic factors for overall survival in endometrial carcinomas (2020)
  • Author(s): Zhang Shuang、Minaguchi Takeo、Xu Chenyang、Qi Nan、Itagaki Hiroya、Shikama Ayumi、Tasaka Nobutaka、Akiyama Azusa、Sakurai Manabu、Ochi Hiroyuki、Satoh Toyomi
  • Journal Title: BMC Cancer Volume: 20 Issue: 1 Pages: 127-127
  • DOI: 10.1186/s12885-020-6545-9
  • NAID: 120007127663
  • Peer Reviewed / Open Access
• [Presentation] PD-L1 EXPRESSION IS AN INDEPENDENT PROGNOSTIC FACTOR FOR SURVIVAL IN ENDOMETRIAL CARCINOMAS (2018)
  • Author(s): Shuang Zhang, Takeo Minaguchi, Ayumi Shikama, Shuling Liu, Bouchra Lachkar, Nobutaka Tasaka, Azusa Akiyama, Manabu Sakurai, Sari Nakao, Hiroyuki Ochi, Toyomi Satoh
  • Organizer: 17th Biennial Meeting of the International Gynecologic Cancer Society
  • Int'l Joint Research
• [Presentation] Survival analyses based on tumor microenvironment profile in endometrial carcinoma (2018)
  • Author(s): Shuang Zhang, Takeo Minaguchi, Ayumi Shikama, Shuling Liu, Bouchra Lachkar, Nobutaka Tasaka, Azusa Akiyama, Manabu Sakurai, Sari Nakao, Hiroyuki Ochi, Toyomi Satoh
  • Organizer: 70th Annual Congress of Japan Society of Obstetrics and Gynecology