Reinforce the antitumor activity of CD8 T cells via restriction of the intracellular glutamine metabolism

2018 Fiscal Year Final Research Report

• Project/Area Number: 17K16853
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Obstetrics and gynecology
• Research Institution: Ehime University
• Principal Investigator: Yasuoka Toshiaki 愛媛大学, 医学部附属病院, 助教 (60648624)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Keywords: 抗腫瘍免疫 / CD8 T細胞 / 細胞内エネルギー代謝

Outline of Final Research Achievements

The antitumor activity of activated CD8 T cells in the tumor microenvironment seems to be limited due to their being metabolically unfit. We therefore assessed the role of glutamine metabolism in the antitumor activity of CD8 T cells using a tumor-inoculated mouse model. The adoptive transfer of tumor-specific CD8 T cells cultured under glutamine-restricted (dGln) conditions or CD8 T cells treated with specific inhibitors of glutamine metabolism efficiently eliminated tumors and led to a better survival of tumor-inoculated mice than with cells cultured under control (Ctrl) conditions. The decreased expression of PD-1 and increased Ki67 positivity among tumor-infiltrating CD8 T cells cultured under dGln conditions suggested that the inhibition of glutamine metabolism prevents CD8 T-cell exhaustion in vivo. Given these findings, our study uncovered an important role of glutamine metabolism in the antitumor activity of CD8 T cells.

Free Research Field

婦人科腫瘍

Academic Significance and Societal Importance of the Research Achievements

グルタミン代謝を抑制したCD8 T細胞の培養を行ったところ、細胞の疲弊が抑制され、通常培養に比べて抗腫瘍活性が増強されることが明らかとなった。そのメカニズムとして、我々は、低グルタミン培養によりCD8 T細胞のメモリー分化が促進することを明らかにした。腫瘍特異的なCD8 T細胞内のグルタミン代謝の抑制は、メモリー分化を促進し、腫瘍微小環境下でも疲弊を免れ増殖を続け、結果として効果的な腫瘍細胞の除去につながると考えられ、腫瘍特異的CD8 T細胞の養子免疫療法として将来、有効な培養方法になることが期待される。