Diurnal Expression of PD-1 on Tumor-Associated Macrophages Underlies the Dosing Time-Dependent Antitumor Effects of the PD-1/PD-L1 Inhibitor BMS-1 in B16/BL6 Melanoma-Bearing Mice

Akito Tsuruta, Yuki Shiiba, Naoya Matsunaga, Marina Fujimoto, Yuya Yoshida, Satoru Koyanagi, Shigehiro Ohdo

研究成果: ジャーナルへの寄稿学術誌査読

2 被引用数 (Scopus)

抄録

Cancer cells have acquired several pathways to escape from host immunity in the tumor microenvironment. Programmed death 1 (PD-1) receptor and its ligand PD-L1 are involved in the key pathway of tumor immune escape, and immune checkpoint therapy targeting PD-1 and PD-L1 has been approved for the treatment of patients with certain types of malignancies. Although PD-1 is a well-characterized receptor on T cells, the immune checkpoint receptor is also expressed on tumor-associated macrophages (TAM), a major immune component of the tumor microenvironment. In this study, we found significant diurnal oscillation in the number of PD-1–expressing TAMs collected from B16/BL6 melanoma-bearing mice. The levels of Pdcd1 mRNA, encoding PD-1, in TAMs also fluctuated in a diurnal manner. Luciferase reporter and bioluminescence imaging analyses revealed that a NF-kB response element in the upstream region of the Pdcd1 gene is responsible for its diurnal expression. A circadian regulatory component, DEC2, whose expression in TAMs exhibited diurnal oscillation, periodically suppressed NF-kB–induced transactivation of the Pdcd1 gene, resulting in diurnal expression of PD-1 in TAMs. Furthermore, the antitumor efficacy of BMS-1, a small molecule inhibitor of PD-1/PD-L1, was enhanced by administering it at the time of day when PD-1 expression increased on TAMs. These findings suggest that identification of the diurnal expression of PD-1 on TAMs is useful for selecting the most appropriate time of day to administer PD-1/PD-L1 inhibitors. Implications: Selecting the most appropriate dosing time of PD-1/ PD-L1 inhibitors may aid in developing cancer immunotherapy with higher efficacy.

本文言語英語
ページ(範囲)972-982
ページ数11
ジャーナルMolecular Cancer Research
20
6
DOI
出版ステータス出版済み - 6月 2022

!!!All Science Journal Classification (ASJC) codes

  • 分子生物学
  • 腫瘍学
  • 癌研究

フィンガープリント

「Diurnal Expression of PD-1 on Tumor-Associated Macrophages Underlies the Dosing Time-Dependent Antitumor Effects of the PD-1/PD-L1 Inhibitor BMS-1 in B16/BL6 Melanoma-Bearing Mice」の研究トピックを掘り下げます。これらがまとまってユニークなフィンガープリントを構成します。

引用スタイル