Exploratory research for immunogenic cell death induced by anti-cancer drugs in lung cancer

2021 Fiscal Year Final Research Report

• Project/Area Number: 19K07733
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50020:Tumor diagnostics and therapeutics-related
• Research Institution: Fukuoka University (2020-2021); Kyushu University (2019)
• Principal Investigator: INOUE HIORYUKI 福岡大学, 医学部, 准教授 (80529967)
• Project Period (FY): 2019-04-01 – 2022-03-31
• Keywords: ICD / DAMP / NSCLC / Calreticulin

Outline of Final Research Achievements

The synergistic effects of immune checkpoint inhibitors and cytotoxic anticancer drugs in the treatment for solid cancers have been implicated in immunogenic cell death (ICD), a process characterized by the release of DAMPs (damage-associated molecular patterns) during cancer cell death. In this study, we found that antimetabolites and microtubule inhibitors induced phosphorylation of Ecto-CRT and eIF2α more strongly than platinum-based anticancer drugs in six human NSCLC cell lines, and a strong positive correlation between Ecto-CRT expression level and apoptosis induction ability. The third generation EGFR-TKI osimertinib also increased Ecto-CRT expression in NSCLC cell lines. In addition, we demonstrated that soluble CRT levels in serum were increased in patients with advanced stage lung cancer treated with pemetrexed/docetaxel monotherapy and osimertinib.

Free Research Field

腫瘍免疫

Academic Significance and Societal Importance of the Research Achievements

本研究結果より、代謝拮抗薬、微小管阻害薬及び第３世代EGFR-TKIオシメルチニブは、複数のNSCLC細胞株におけるEcto-CRT発現量及びNSCLC患者血液中の可溶性CRTを効果的に誘導し、これらの薬剤は長期抗腫瘍効果を期待できるICIを含む複合免疫療法において、ICDを誘導することで抗腫瘍免疫効果の増強に寄与している可能性が示唆された。また、今後CRTのみでなくその他のDAMP分子を含む統合解析により、これらDAMP分子が治療効果予測バイオマーカーとなりうる可能性も示唆された。現在我々は、血中DAMP分子値とICI治療効果の相関解析を進めている。