Elucidation of the Mechanism of Topotecan-induced Antitumor Immune Activation

Abstract

Danger-associated molecular patterns (DAMPs) derived from damaged or dying cells elicit inflammation and potentiate antitumor immune responses. We found that treatment of cancer cells with the antitumor agent topotecan (TPT), an inhibitor of topoisomerase I (TOP1), induces DAMP secretion that triggers dendritic cell activation and cytokine production. TPT administration inhibits tumor growth in tumor-bearing mice, which is accompanied by infiltration of activated DCs and CD8+ T cells. These effects are abrogated in mice lacking stimulator of interferon genes (STING), an essential molecule in cytosolic DNA-mediated innate immune responses. Furthermore, we identified ribosomal protein L15 (RPL15), a 60S ribosomal protein, as a novel TPT target and showed that TPT inhibited pre-ribosomal subunit formation via its binding to RPL15, resulting in the induction of DAMP-mediated antitumor immune activation independent of TOP1. RPL15 knockdown induced DAMP secretion and increased the cytotoxic T lymphocyte (CTL) population but decreased the T-regulatory cell (Treg) population in a B16-F10 murine melanoma model, which sensitized B16-F10 tumors against programmed death receptor-1(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.