Analysis of Tumor Immunosuppressive Mechanisms in the Oral Cancer Invasive Microenvironment.

2019 Fiscal Year Final Research Report

• Project/Area Number: 17K11869
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Surgical dentistry
• Research Institution: Kanazawa University
• Principal Investigator: Nakamura Hiroyuki 金沢大学, 医学系, 准教授 (30542253)
• Co-Investigator(Kenkyū-buntansha): 北原 寛子 金沢大学, 附属病院, 医員 (70507053)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Keywords: MMP / PD-L1

Outline of Final Research Achievements

In this study, we adressed to 1; identify MMPs that are reduced in expression during EMT-induced formation of type 4D highly invasive oral cancer cells and cancer-associated fibroblasts; 2; investigate their degradative activity against PD-L1. 3; identify cleavage sites. 4; among MMPs that degrade PD-L1, we identified MMPs that suppress T-cell immune tolerance. 5; in addition, the tumor immune activation effects of MMP in the cancer microenvironment were verified using 4D type high invasion oral cancer cell which stably expresses MMP which suppresses this immune tolerance and selective MMP synthetic inhibitors.
We verified whether type 4D highly invasive oral cancer cells at the invasive front were transformed into minimally invasive cancer by tumor immunity activated with MMPs using a murine oral cancer invasive metastatic model.

Free Research Field

口腔癌

Academic Significance and Societal Importance of the Research Achievements

本研究で明らかにされるPD-L1を分解するMMPの発現が亢進している癌組織では、すでに免疫寛容が抑制されている可能性があり、この場合ニボルマブの効果が期待できないだけでなく、投与により過剰な免疫反応等の副作用を引き起こす可能性がある。したがってこの場合、ニボルマブ使用適正患者を選定する際の有効なバイオマーカーとしてMMPが有用であると期待される。ま本研究から得られる結果はMMPインヒビターによる癌治療の挫折を乗り越えて、近年急速に注目されている癌免疫療法の有効性を高めるための有益な情報を与える点で意義がある。