Identification of RPL15 60S Ribosomal Protein as a Novel Topotecan Target Protein That Correlates with DAMP Secretion and Antitumor Immune Activation

  • J Immunol. 2022 Jul 1;209(1):171-179. doi: 10.4049/jimmunol.2100963.
Shunsuke Yamada  1 ,  Yuichi Kitai  2 ,  Takashi Tadokoro  3 ,  Runa Takahashi  1 ,  Haruka Shoji  1 ,  Taiga Maemoto  1 ,  Marie Ishiura  1 ,  Ryuta Muromoto  1 ,  Jun-Ichi Kashiwakura  1 ,  Ken J Ishii  4  5  6 ,  Katsumi Maenaka  3  7 ,  Taro Kawai  8 ,  Tadashi Matsuda  2
Affiliations
  • 1. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo, Hokkaido, Japan.
  • 2. Department of Immunology, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo, Hokkaido, Japan; [email protected] [email protected].
  • 3. Faculty of Pharmaceutical Sciences, Hokkaido University, Kita-Ku, Sapporo, Hokkaido, Japan.
  • 4. Division of Vaccine Science, Department of Microbiology and Immunology, The Institute of Medical Science, The University of Tokyo, Minato-ku, Tokyo, Japan.
  • 5. Laboratory of Mockup Vaccine, Center for Vaccine and Adjuvant Research, National Institutes of Biomedical Innovation, Health and Nutrition, Saito, Ibaraki, Osaka, Japan.
  • 6. Laboratory of Vaccine Science, WPI Immunology Frontier Research Center, Osaka University, Yamadaoka, Suita, Osaka, Japan.
  • 7. Global Station for Biosurfaces and Drug Discovery, Hokkaido University, Kita-Ku, Sapporo, Japan; and.
  • 8. Laboratory of Molecular Immunobiology, Division of Biological Science, Graduate School of Science and Technology, Nara Institute of Science and Technology, Ikoma, Nara, Japan.
PMID: 35725272 DOI: 10.4049/jimmunol.2100963
Abstract

Damage-associated molecular patterns (DAMPs) contribute to antitumor immunity during Cancer chemotherapy. We previously demonstrated that topotecan (TPT), a Topoisomerase I inhibitor, induces DAMP secretion from Cancer cells, which activates STING-mediated antitumor immune responses. However, how TPT induces DAMP secretion in Cancer cells is yet to be elucidated. Here, we identified RPL15, a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited preribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. TPT inhibits RPL15-RPL4 interactions and decreases RPL4 stability, which is recovered by CDK12 activity. RPL15 knockdown induced DAMP secretion and increased the CTL population but decreased the regulatory T cell population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against PD-1 blockade. Our study identified a novel TPT target protein and showed that ribosomal stress is a trigger of DAMP secretion, which contributes to antitumor immunotherapy.

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