Singularity cells in immunity and cancer development

2022 Fiscal Year Final Research Report

• Project Area: Singularity biology
• Project/Area Number: 18H05417
• Research Category: Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)
• Allocation Type: Single-year Grants
• Review Section: Complex systems
• Research Institution: The University of Tokyo (2020-2022); The University of Tokushima (2018-2019)
• Principal Investigator: Okazaki Taku 東京大学, 定量生命科学研究所, 教授 (00362468)
• Co-Investigator(Kenkyū-buntansha): 片貝 智哉 新潟大学, 医歯学系, 教授 (00324682)
• Project Period (FY): 2018-06-29 – 2023-03-31
• Keywords: 免疫補助受容体 / 自己免疫 / がん免疫 / シンギュラリティ生物学

Outline of Final Research Achievements

First, we demonstrated that autoreactive CD8+ T cells in NOD mice went through four activation phases and PD-1 strongly attenuated the transition from the second to the third phase, where effector functions were acquired by analyzing their activation trajectory. Next, we found that T cell receptor (TCR) signal strength required for the induction of genes varies across different genes and PD-1 preferentially inhibits the induction of genes that require stronger TCR signal. We further demonstrated that PD-1 inhibits the expression of TCR-inducible genes efficiently when the affinity between TCR and peptide-MHC complex is low. These results indicate that inhibitory co-receptors do not weaken T cell responses uniformly, but they impose qualitative control of T cell responses. We also revealed the establishment of immuno-suppressive environment in tumors and draining lymph nodes during the early phase of tumor development, which attenuates the proliferation of tumor-specific T cells.

Free Research Field

免疫学

Academic Significance and Societal Importance of the Research Achievements

抑制性免疫補助受容体PD-1を標的としたがん免疫療法の成功により、がんに対する免疫療法が大きな関心を集めているが、奏効率の向上と自己免疫様の副作用の軽減が課題となっている。がんや自己組織に対する免疫応答が進行するメカニズムが解明されることにより、より効果的かつ安全な治療法の開発が促進されると期待される。