NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations
Summary: 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...
| Main Authors: | , , , , , , |
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| Format: | Article |
| Language: | English |
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Elsevier
2022-11-01
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| Series: | iScience |
| Subjects: | |
| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004222016984 |
| _version_ | 1828191273745383424 |
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| author | Yi Le Hong Gao Angie Zhu Kristen Felt Scott Rodig Ronald Bleday Zhenglun Zhu |
| author_facet | Yi Le Hong Gao Angie Zhu Kristen Felt Scott Rodig Ronald Bleday Zhenglun Zhu |
| author_sort | Yi Le |
| collection | DOAJ |
| description | Summary: 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. |
| first_indexed | 2024-04-12T08:36:11Z |
| format | Article |
| id | doaj.art-4debbb58e93942a297c34046442264bd |
| institution | Directory Open Access Journal |
| issn | 2589-0042 |
| language | English |
| last_indexed | 2024-04-12T08:36:11Z |
| publishDate | 2022-11-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj.art-4debbb58e93942a297c34046442264bd2022-12-22T03:40:01ZengElsevieriScience2589-00422022-11-012511105426NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrationsYi Le0Hong Gao1Angie Zhu2Kristen Felt3Scott Rodig4Ronald Bleday5Zhenglun Zhu6Department of Medicine, Brigham and Women’s Hospital, Boston, MA, USADepartment of Medicine, Tufts Medical Center, Boston, MA, USADepartment of Medicine, Brigham and Women’s Hospital, Boston, MA, USADepartment of Pathology, Brigham and Women’s Hospital, Boston, MA, USADepartment of Pathology, Brigham and Women’s Hospital, Boston, MA, USADepartment of Surgery, Brigham and Women’s Hospital, Boston, MA, USADepartment of Medicine, Brigham and Women’s Hospital, Boston, MA, USA; Corresponding authorSummary: 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.http://www.sciencedirect.com/science/article/pii/S2589004222016984Molecular biologyImmunologyCell biologyCancer |
| spellingShingle | Yi Le Hong Gao Angie Zhu Kristen Felt Scott Rodig Ronald Bleday Zhenglun Zhu NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations iScience Molecular biology Immunology Cell biology Cancer |
| title | NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations |
| title_full | NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations |
| title_fullStr | NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations |
| title_full_unstemmed | NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations |
| title_short | NF-κB-regulated VentX expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations |
| title_sort | nf κb regulated ventx expression mediates tumoricidal effects of chemotherapeutics at noncytotoxic concentrations |
| topic | Molecular biology Immunology Cell biology Cancer |
| url | http://www.sciencedirect.com/science/article/pii/S2589004222016984 |
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