Development of novel cancer immunotherapy by induction of epithelial-tropic CD8 T cells

• Project/Area Number: 20K07556
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 49070:Immunology-related
• Research Institution: Kindai University
• Principal Investigator: Takamura Shiki 近畿大学, 医学部, 講師 (90528564)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Project Status: Completed (Fiscal Year 2022)
• Budget Amount: ¥4,290,000 (Direct Cost: ¥3,300,000、Indirect Cost: ¥990,000); Fiscal Year 2022: ¥1,300,000 (Direct Cost: ¥1,000,000、Indirect Cost: ¥300,000); Fiscal Year 2021: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2020: ¥1,560,000 (Direct Cost: ¥1,200,000、Indirect Cost: ¥360,000)
• Keywords: 免疫記憶 / 滞在型メモリー / CD8T細胞 / ウイルス感染防御 / メモリーCD8T細胞 / インフルエンザウイルス / 肺粘膜 / 感染防御

Outline of Research at the Start

肺粘膜に定着する滞在型メモリーCD8T細胞（CD8TRM）は様々な株のインフルエンザウイルスに対して感染防御効果を示す。従って、効果的な肺CD8TRM誘導・維持が新規ワクチン開発の重要な課題である。研究代表者は先行研究にて肺におけるCD8TRM分化部位を同定したが、同部位が早期に消失することでCD8TRMによる防御効果も失われてしまうことも判明した。本研究では「肺CD8TRM維持期間の延長」を最終目的とし、TRM維持に関与する肺マクロファージ及び樹状細胞の機能を解析する。また、粘膜脂質代謝環境変化の誘導によるCD8TRM維持期間の延長効果、肺CD8 RM増幅誘導による長期維持効果を検討する。

Outline of Final Research Achievements

Although tissue-resident memory CD8 T cells (CD8 TRMs) in the lung mucosa confer localized protection against challenges with various strains of influenza viruses, their longevity is shorter than that of other tissues. In this study, we aimed to elucidate the differentiation and maintenance mechanisms of pulmonary CD8 TRMs in order to extend their longevity. First, we found that pulmonary macrophages promote TRM differentiation by providing local antigen stimulation in the early stages of infection. We also found that the lung CD8 TRM is maintained in an autophagy-independent manner even during starvation. We also found that when long-term antigen presentation is induced following intranasal immunization with adenovirus vectors. As a result, circulating memory T cells are continuously activated and differentiate into TRM in the lung. Understanding the mechanisms by which prolonged antigen presentation would help in the development of vaccination strategies to generate long-lived TRM.

Academic Significance and Societal Importance of the Research Achievements

現行のインフルエンザワクチンにより誘導される免疫応答は特定の株に対する全身性抗体反応であり、侵入部位である肺局所での感染防御効果は期待できない。また、パンデミックの要因となる大規模の変異は勿論、季節性インフルエンザウイルス株間にて頻繁に起こる小規模なウイルス表面タンパクの変異にも対応が困難であり、新規ワクチン開発が急務である。感染局所に定着する滞在型メモリーCD8 T細胞（CD8 TRM）は二次感染時に局所にて感染細胞を早期破壊することで防御免疫の最前線を担う。従って、肺粘膜にてCD8 TRMを効果的に分化誘導することが交差反応型ワクチン開発における最重要課題である。

Research Products

• [Int'l Joint Research] Mayo Clinic(米国)
• [Int'l Joint Research] エモリー大学(米国)
• [Int'l Joint Research] コペンハーゲン大学(デンマーク)
• [Journal Article] Disruption of the intestinal barrier exacerbates experimental autoimmune pancreatitis by promoting the translocation of <i>Staphylococcus sciuri</i> into the pancreas (2022)
  • Author(s): Yoshikawa Tomoe、Minaga Kosuke、Hara Akane、Sekai Ikue、Kurimoto Masayuki、Masuta Yasuhiro、Otsuka Yasuo、Takada Ryutaro、Kamata Ken、Park Ah-Mee、Takamura Shiki、Kudo Masatoshi、Watanabe Tomohiro
  • Journal Title: International Immunology Volume: 34 Issue: 12 Pages: 621-634
  • DOI: 10.1093/intimm/dxac039
  • Peer Reviewed
• [Journal Article] Alveolar macrophages instruct CD8+ T cell expansion by antigen cross-presentation in lung. (2022)
  • Author(s): Kawasaki T, Ikegawa M, Yunoki K, Otani H, Ori D, Ishii KJ, Kuroda E, Takamura S, Kitabatake M, Ito T, Isotani A, Kawai T.
  • Journal Title: Cell Rep Volume: 41 Issue: 11 Pages: 111828-111828
  • DOI: 10.1016/j.celrep.2022.111828
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Vaccine Based on Dendritic Cells Electroporated with an Exogenous Ovalbumin Protein and Pulsed with Invariant Natural Killer T Cell Ligands Effectively Induces Antigen-Specific Antitumor Immunity (2022)
  • Author(s): Watanabe Akihiro
  • Journal Title: Cancers Volume: 14(1) Issue: 1 Pages: 171-188
  • DOI: 10.3390/cancers14010171
  • Peer Reviewed / Open Access
• [Journal Article] Editorial: Resident memory T cells Guardians of the balance between local immunity and pathology. (2021)
  • Author(s): Goplen NP, Takamura S Nakayama T, Sun J.
  • Journal Title: Front. Immunol. Volume: 12 Pages: 745256-745256
  • DOI: 10.3389/fimmu.2021.745256
  • Peer Reviewed / Open Access
• [Journal Article] Long-term maintenance of lung resident memory T cells is mediated by persistent antigen (2021)
  • Author(s): Uddback I, Cartwright EK, Scholler AS, Wein AN, Hayward SL, Lobby J, Takamura S, Thomsen AR, Kohlmeier JK, Christensen JP
  • Journal Title: Mucosal Immunol. Volume: 14(1) Issue: 1 Pages: 92-99
  • DOI: 10.1038/s41385-020-0309-3
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Divergence of tissue-memory T cells: Distribution and function-based classification (2020)
  • Author(s): Takamura S
  • Journal Title: Cold Spring Harb. Perspect. Biol. Volume: 12(19) Issue: 10 Pages: a037762-a037762
  • DOI: 10.1101/cshperspect.a037762
  • Peer Reviewed
• [Journal Article] Impact of multiple hits with cognate antigen on memory CD8+ T cell fate (2020)
  • Author(s): Takamura S
  • Journal Title: Int. Immunol. Volume: 32(9) Issue: 9 Pages: 571-581
  • DOI: 10.1093/intimm/dxaa039
  • Peer Reviewed
• [Journal Article] Environmental cues regulate epigenetic reprograming of airway-resident memory CD8 T cells (2020)
  • Author(s): 4. Hayward SL, Scharer CD, Cartwright EK, Takamura S, Tiger li ZR, Boss JM, Kohlmeier JK
  • Journal Title: Nat. Immunol. Volume: 21(3) Issue: 3 Pages: 309-320
  • DOI: 10.1038/s41590-019-0584-x
  • Peer Reviewed
• [Journal Article] Pulmonary monocytes interact with effector T cells in the lung tissue to drive TRM differentiation following viral infection (2020)
  • Author(s): Dunbar Paul R.、Cartwright Emily K.、Wein Alexander N.、Tsukamoto Tetsuo、Tiger Li Zheng-Rong、Kumar Nivedha、Uddb?ck Ida E.、Hayward Sarah L.、Ueha Satoshi、Takamura Shiki、Kohlmeier Jacob E.
  • Journal Title: Mucosal Immunology Volume: 13 Issue: 1 Pages: 161-171
  • DOI: 10.1038/s41385-019-0224-7
  • Peer Reviewed / Int'l Joint Research
• [Presentation] Generation and maintenance of epithelial-tropic CD8+ T cells in the peripheral tissues and tumor (2022)
  • Author(s): Takamura S
  • Organizer: 第51回 日本免疫学会総会・学術集会 国際シンポジウム
  • Int'l Joint Research / Invited
• [Presentation] Maintenance of tissue-resident memory CD8+ T cells in the lung (2021)
  • Author(s): Takamura S
  • Organizer: The 5th Symposium of International Immunological Memory and Vaccine Forum “Educating the immune system: Good and bad memory”
  • Int'l Joint Research / Invited
• [Remarks] 近畿大学医学部免疫学教室
  • URL: https://www.med.kindai.ac.jp/immuno/