NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations

Yi Le; Hong Gao; Angie Zhu; Kristen Felt; Scott Rodig; Ronald Bleday; Zhenglun Zhu

doi:10.1016/j.isci.2022.105426

NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations

iScience. 2022 Oct 22;25(11):105426. doi: 10.1016/j.isci.2022.105426. eCollection 2022 Nov 18.

Authors

Yi Le¹, Hong Gao², Angie Zhu¹, Kristen Felt³, Scott Rodig³, Ronald Bleday⁴, Zhenglun Zhu¹

Affiliations

¹ Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA.
² Department of Medicine, Tufts Medical Center, Boston, MA, USA.
³ Department of Pathology, Brigham and Women's Hospital, Boston, MA, USA.
⁴ Department of Surgery, Brigham and Women's Hospital, Boston, MA, USA.

Abstract

Limited therapeutic efficacy and severe side effects represent the central hurdles facing cancer chemotherapy. Immune suppression within tumor immune microenvironments (TIME) has been implicated in chemoresistance. In this study, using a TIME-enabling model system (TIME-EMS), we demonstrate that the chemotherapeutic agent doxorubicin has cytocidal effects on tumor cells at high dosage but induces changes in the immune landscape of the TIME at low noncytotoxic concentrations via NF-κB-mediated induction of homeobox protein VentX expression in tumor-associated macrophages (TAMs). We demonstrated that VentX-regulated TAMs drastically promote tumor chemosensitivity >10-fold but exert little effect on chemotoxicity to normal cells through activating cytotoxic T lymphocytes in a tumor-specific manner. Supported by the in vivo synergy of VentX-regulated TAMs and low-dosage noncytotoxic doxorubicin, our data suggest a cell-death-independent immune mechanism for improving the therapeutic index of chemotherapeutic agents.

Keywords: Cancer; Cell biology; Immunology; Molecular biology.