The mechanism of age-related unresponsiveness to PD-1 blockade cancer therapy

2022 Fiscal Year Final Research Report

• Project/Area Number: 20K07615
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Review Section: Basic Section 50010:Tumor biology-related
• Research Institution: Foundation for Biomedical Research and Innovation at Kobe (2021-2022); Kyoto University (2020)
• Principal Investigator: Waku Yuka (仲島由佳) 公益財団法人神戸医療産業都市推進機構, その他部局等, 研究員 (40399499)
• Project Period (FY): 2020-04-01 – 2023-03-31
• Keywords: 免疫老化

Outline of Final Research Achievements

Recent reports showed that the efficacy of PD-1 blockade cancer therapy is impaired in aged-animal models, with similar attenuation to that observed in some clinical reports. However, the mechanism underlying this age-related decrease in the efficacy of PD-1 blockade remains largely unknown.
Previously, we found that suppression of a subset of CD8+ T-cells (CD44lowCD62Llow subset P4) correlates with resistance to PD-1 blockade anti-tumor therapy in aged mice. In this study, our data showed that reduced emergence of P4 cells was caused by the depression of P4 cell differentiation from naive cells, and thereby inhibited one-carbon metabolism in CD8+ T cells from aged mice. Moreover, our results suggest that elevated expression of the suppressive phosphatase is responsible for the lack of P4 cells through the inhibition of TCR pathway, which is linked to reduce the efficacy of PD-1 blockade therapy.

Free Research Field

腫瘍免疫

Academic Significance and Societal Importance of the Research Achievements

免疫系の老化は、がんの発症や進展のみならず、感染症や関節リウマチ、動脈硬化などの加齢関連疾患の発症や病態形成に重要な役割を果たすことが明らかになってきている。そのため、本研究成果から得られる免疫老化とその改善に関する知見は、新しいがん免疫治療法の開発につながるだけではなく、様々な加齢関連疾患に対する新たな診断マーカーや治療基盤の創出につながると考えられるものである。