Inhibition of topoisomerase I shapes antitumor immunity through the induction of monocyte-derived dendritic cells

Abstract

Understanding the rationale of combining immunotherapy and other anticancer treatment modalities is of great interest because of interpatient variability in single-agent immunotherapy. Here, we demonstrated that topoisomerase I inhibitors, a class of chemotherapeutic drugs, can alter the tumor immune landscape, corroborating their antitumor effects combined with immunotherapy. We observed that topotecan-conditioned TC-1 tumors were occupied by a vast number of monocytic cells that highly express CD11c, CD64, and costimulatory molecules responsible for the favorable changes in the tumor microenvironment. Ly6C⁺MHC-II⁺CD11c^hiCD64^hi cells, referred to as topotecan-induced monocyte-derived dendritic cells (moDCs), proliferate and activate antigen-specific CD8⁺ T cells to levels equivalent to those of conventional DCs. Phenotypic changes in Ly6C⁺ cells towards moDCs were similarly induced by exposure to topotecan in vitro, which was more profoundly facilitated in the presence of tumor cells. Notably, anti-M-CSFR reversed the acquisition of DC-like properties of topotecan-induced moDCs, leading to the abolition of the antitumor effect of topotecan combined with a cancer vaccine. In short, topoisomerase I inhibitors generate monocyte-derived antigen-presenting cells in tumors, which could be mediated by M-CSF-M-CSFR signaling.

Keywords: Cancer vaccine; Chemoimmunotherapy; Combination cancer therapy; Monocyte-derived dendritic cells; Topoisomerase I inhibitors.