Regulatory Mechanisms of Immune Tolerance in the Highly Invasive Oral Cancer Microenvironment

2021 Fiscal Year Final Research Report

• Project/Area Number: 20K18664
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 57060:Surgical dentistry-related
• Research Institution: University of the Ryukyus (2021); Kanazawa University (2020)
• Principal Investigator: Hirai Mariko 琉球大学, 医学(系)研究科(研究院), 客員研究員 (40802830)
• Project Period (FY): 2020-04-01 – 2022-03-31
• Keywords: 口腔癌

Outline of Final Research Achievements

Oral squamous cell carcinoma cells were induced into type 4D highly invasive oral cancer cells by EMT. We analyzed changes in MMP expression in these cultured cells to determine which MMPs were down-regulated by EMT induction and identified MMPs with PD-L1 cleavage activity by examining PD-L1 cleaved from the plasma membrane in the culture supernatant of HEK293 cells, which stably express MMPs and PD-L1. An expression vector for secreted PD-L1 was generated and PD-L1 recombinant protein was purified. The purified PD-L1 was incubated with recombinant MMPs to identify MMPs with PD-L1-degrading activity. Existing anticancer agents were added to several types of cultured oral cancer cells to determine which anticancer agents upregulate MMP expression.

Free Research Field

口腔外科

Academic Significance and Societal Importance of the Research Achievements

高転移性高浸潤型の口腔扁平上皮癌の浸潤先端部では、僅か数個の癌細胞が周囲微小環境で免疫寛容を成立させ腫瘍免疫から逃れ生存している。よって、高転移性高浸潤口腔癌は予後不良で根本的な治療が困難である。近年、癌免疫療法が注目され、高転移性高浸潤型口腔癌でもニボルマブ（抗PD-1抗体）の持続的な効果が示されているが有効である患者は一部に限定される。本研究結果は、効果を予測するマーカーの開発や、ニボルマブ不応や耐性となった後の治療体系の確立に貢献し、高転移性高浸潤口腔癌の浸潤先端部微小環境での免疫寛容調節機構の解明に重要な情報を提供する。