Metabolite secretome of necrotic tumor cells contributes to T cell dysfunction in cancer

2020 Fiscal Year Final Research Report

• Project/Area Number: 19K16736
• Research Category: Grant-in-Aid for Early-Career Scientists
• Allocation Type: Multi-year Fund
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: The University of Tokyo
• Principal Investigator: Hibino Sana 東京大学, 先端科学技術研究センター, 特別研究員 (30836424)
• Project Period (FY): 2019-04-01 – 2021-03-31
• Keywords: T細胞 / 腫瘍免疫 / オンコメタボライト / ポリアミン

Outline of Final Research Achievements

Solid tumors often undergo massive necrotic cell death during disease progression as a result of enforced exposure to the severe microenvironment such as hypoxia and nutrient starvation. Here we demonstrate that necrotic tumor cells release arrays of immunosuppressive metabolites into the extracellular fluids, which cooperatively inhibit T cell effector function. Notably, we elucidate a novel role for the major polyamine Spermidine; intracellular spermidine function as an essential metabolic fuel in growing cancer cells, but extracellular spermidine also contribute to tumor progression by dampening downstream T cell receptor signaling and c-Myc-driven effector programs under in vivo situations. Additionally, pharmacological inhibition of polyamine synthesis effectively invigorates tumor-infiltrating CD8+ T cells and breaks resistance to anti-PD-1 therapy in mice. Thus, targeting the “metabolite secretome” of necrotic tumor cells can be a promising approach in cancer immunotherapy.

Free Research Field

腫瘍免疫学

Academic Significance and Societal Importance of the Research Achievements

CD8+ T細胞は抗腫瘍免疫応答の要となるが、固形がんの局所に浸潤しているT細胞の多くは、がんに対する攻撃力を失った“機能不全”状態にある。腫瘍浸潤T細胞が機能不全に至るプロセスの分子基盤、特にがん細胞側の因子の関与については未だ不明な点が多い。本研究より、腫瘍局所には細胞死を起こしたがん細胞から放出される免疫抑制性の低分子代謝物が豊富に存在し、CD8+ T細胞の機能抑制に寄与している可能性が示された。ネクローシス癌細胞の代謝物セクレトームは、がん免疫療法における新規治療標的として期待できる。