Effects of steroids on anti-tumor immune response induced by immune checkpoint inhibitors

• Project/Area Number: 17K15738
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Immunology
• Research Institution: National Cancer Center Japan
• Principal Investigator: Maeda Yuka 国立研究開発法人国立がん研究センター, 研究所, 主任研究員 (20757223)
• Project Period (FY): 2017-04-01 – 2021-03-31
• Project Status: Completed (Fiscal Year 2020)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2020: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000); Fiscal Year 2017: ¥1,170,000 (Direct Cost: ¥900,000、Indirect Cost: ¥270,000)
• Keywords: 免疫チェックポイント阻害剤 / irAE / ステロイド / 免疫抑制 / 免疫療法 / 免疫学

Outline of Final Research Achievements

The results of cancer treatment with immune checkpoint inhibitors are remarkable in limited patients. However, immune checkpoint inhibitors are also associated with serious side effects, especially immune related adverse events (irAEs), which are often deleterious. Although steroids, which are immunosuppressive agents, are the basic treatment for irAEs, the effect of steroids on the anti-tumor immune response has not been investigated in detail. In the present study, we demonstrated for the first time that steroid treatment of irAEs induced by immune checkpoint inhibitors prevents the synthesis of memory T cells against these antigens in the presence of shared antigens. Furthermore, steroids inhibit the synthesis of memory T cells with low-affinity TCR through the fatty acid metabolism pathway.

Academic Significance and Societal Importance of the Research Achievements

Neo抗原が多い患者は免疫チェックポイント阻害剤が効きやすいという報告は多い。しかし本研究から、これまでの単純な“奏功と副作用のコントロール”の理解から一歩踏み込んだ見解を得た。免疫療法が奏功しメモリーT細胞が機能している患者に対しては、irAEが生じてもステロイド剤によるNeo抗原特異的メモリーT細胞合成阻害が生じないため、抗腫瘍免疫応答は影響を受けず、自己に対する過剰な免疫応答であるirAEのみを抑えることができると考えられる。医師らが、ステロイド投与によって生じる生理現象を深く理解することは、がん免疫療法が安全かつ適切に取り扱われる事であり、結果として質の高い医療の提供に繋がる。

Research Products

• [Journal Article] The PD-1 expression balance between effector and regulatory T cells predicts the clinical efficacy of PD-1 blockade therapies (2020)
  • Author(s): Kumagai S,Togashi Y,Kamada T,Sugiyama E,Nishinakamura H,Takeuchi Y,Vitaly K,Itahashi K,Maeda Y,Matsui S,Shibahara T,Yamashita Y,Irie T,Tsuge A,Fukuoka S,Kawazoe A,Udagawa H,Kirita K,Aokage K,Ishii G,Kuwata T,Nakama K,Kawazu M,Ueno T,Yamazaki N,Goto K,Tsuboi M,Mano H,Doi T,Shitara K,Nishikawa H
  • Journal Title: Nature Immunology Volume: 21 Issue: 11 Pages: 1346-1358
  • DOI: 10.1038/s41590-020-0769-3
  • Peer Reviewed / Open Access
• [Journal Article] Model-based clustering for flow and mass cytometry data with clinical information (2020)
  • Author(s): Abe K, Minoura K, Maeda Y, Nishikawa H, Shimamura T§
  • Journal Title: BMC Bioinformatics Volume: 21(Suppl 13) Issue: S13 Pages: 393-393
  • DOI: 10.1186/s12859-020-03671-7
  • Peer Reviewed / Open Access
• [Journal Article] CYBERTRACK2.0: zero-inflated model-based cell clustering and population tracking method for longitudinal mass cytometry data (2020)
  • Author(s): Minoura K*, Abe K*, Maeda Y, Nishikawa H, Shimamura T§
  • Journal Title: Bioinformatics Volume: - Issue: 11 Pages: 873-873
  • DOI: 10.1093/bioinformatics/btaa873
  • Peer Reviewed / Open Access
• [Journal Article] Adult-Onset Anti-Citrullinated Peptide Antibody-Negative Destructive Rheumatoid Arthritis Is Characterized by a Disease-Specific CD8+ T Lymphocyte Signature (2020)
  • Author(s): Kelkka T, Savola P, Bhattacharya D, Huuhtanen J, Lonnberg T, Kankainen M, Paalanen K, Tyster M, Lepisto M, Ellonen P, Smolander J, Eldfors S, Yadav B, Khan S, Koivuniemi R, Sjowall C, Elo LL, Lahdesmaki H, Maeda Y, Nishikawa H, Leirisalo-Repo M, Sokka-Isler T, Mustjoki S.
  • Journal Title: Front Immunol. Volume: -
  • DOI: 10.3389/fimmu.2020.578848
  • Peer Reviewed
• [Journal Article] Selective inhibition of low-affinity memory CD8+ T cells by corticosteroids (2019)
  • Author(s): Tokunaga Akihiro、Sugiyama Daisuke、Maeda Yuka、Warner Allison Betof、Panageas Katherine S.、Ito Sachiko、Togashi Yosuke、Sakai Chika、Wolchok Jedd D.、Nishikawa Hiroyoshi
  • Journal Title: Journal of Experimental Medicine Volume: 216 Issue: 12 Pages: 2701-2713
  • DOI: 10.1084/jem.20190738
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Presentation] Elucidation of the antigen-specific immunosuppression mechanism in the tumor microenvironment (2020)
  • Author(s): 前田優香
  • Organizer: 第79回日本癌学会学術総会
• [Presentation] 免疫抑制-制御性T細胞とステロイド (2018)
  • Author(s): 前田優香
  • Organizer: 第28回日本色素細胞学会
  • Invited
• [Presentation] がん免疫-基礎研究から臨床応用の可能性 (2018)
  • Author(s): 前田優香
  • Organizer: 第58回日本リンパ網内系学会総会
  • Invited