Key Points
RPL15 is identified as a novel TPT target.
TPT induces DAMP secretion from cancer cells via its binding to RPL15.
RPL15 inhibition sensitizes B16-F10 tumors against PD-1 blockade.
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.
Footnotes
S.Y., Y.K., R.T., H.S., T. Maemoto, and M.I. performed experiments. T.T., R.M., J.K., K.J.I., K.M., T.K., and T. Matsuda analyzed data. Y.K. designed experiments, supervised the project, and wrote the paper.
This work was supported by a Grant-in-Aid for Early-Career Scientists (Y.K.), research grants from Takeda Science Foundation (Y.K.), the Promotion for Young Research Talent and Network from Northern Advancement Center for Science and Technology (Y.K.), and in part by Grant-in-Aid for Scientific Research (B) (T. Matsuda). This work was the result of using research equipment shared in the Japan Society for the Promotion of Science project for promoting public use of advanced research infrastructure (program for supporting introduction of the new sharing system) Grant JPMXS0420100119. This research was partially supported by Platform Project for Supporting Drug Discovery and Life Science Research (Basis for Supporting Innovative Drug Discovery and Life Science Research) from Japan Agency for Medical Research and Development under Grant JP19am0101093 (support number 1234).
The online version of this article contains supplemental material.
- Received October 7, 2021.
- Accepted April 16, 2022.
- Copyright © 2022 by The American Association of Immunologists, Inc.
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