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

2022 Fiscal Year Final Research Report

• 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
• Keywords: 免疫記憶 / 滞在型メモリー / CD8T細胞 / ウイルス感染防御

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.

Free Research Field

免疫学

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。