β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers
NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. β-Lapachone (β-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD)...
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Taylor & Francis Group
2024-12-01
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| Series: | OncoImmunology |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2363000 |
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| author | Soumya Tumbath Lingxiang Jiang Xiaoguang Li Taolan Zhang Kashif Rafiq Zahid Ye Zhao Hao Zhou Zhijun Yin Tao Lu Shu Jiang Yaomin Chen Xiang Chen Yang-Xin Fu Xiumei Huang |
| author_facet | Soumya Tumbath Lingxiang Jiang Xiaoguang Li Taolan Zhang Kashif Rafiq Zahid Ye Zhao Hao Zhou Zhijun Yin Tao Lu Shu Jiang Yaomin Chen Xiang Chen Yang-Xin Fu Xiumei Huang |
| author_sort | Soumya Tumbath |
| collection | DOAJ |
| description | NAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. β-Lapachone (β-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD) and enhancing tumor immunogenicity. However, the interaction between β-Lap-mediated antitumor immune responses and neutrophils, novel antigen-presenting cells (APCs), remains unknown. This study demonstrates that β-Lap selectively kills NQO1-positive murine tumor cells by significantly increasing intracellular ROS formation and inducing DNA double strand breaks (DSBs), resulting in DNA damage. Treatment with β-Lap efficiently eradicates immunocompetent murine tumors and significantly increases the infiltration of tumor-associated neutrophils (TANs) into the tumor microenvironment (TME), which plays a crucial role in the drug’s therapeutic efficacy. Further, the presence of β-Lap-induced antigen medium leads bone marrow-derived neutrophils (BMNs) to directly kill murine tumor cells, aiding in dendritic cells (DCs) recruitment and significantly enhancing CD8+ T cell proliferation. β-Lap treatment also drives the polarization of TANs toward an antitumor N1 phenotype, characterized by elevated IFN-β expression and reduced TGF-β cytokine expression, along with increased CD95 and CD54 surface markers. β-Lap treatment also induces N1 TAN-mediated T cell cross-priming. The HMGB1/TLR4/MyD88 signaling cascade influences neutrophil infiltration into β-Lap-treated tumors. Blocking this cascade or depleting neutrophil infiltration abolishes the antigen-specific T cell response induced by β-Lap treatment. Overall, this study provides comprehensive insights into the role of tumor-infiltrating neutrophils in the β-Lap-induced antitumor activity against NQO1-positive murine tumors. |
| format | Article |
| id | doaj-art-949b1bfe9fef4f57be1db5d9a66f7789 |
| institution | Kabale University |
| issn | 2162-402X |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | OncoImmunology |
| spelling | doaj-art-949b1bfe9fef4f57be1db5d9a66f77892024-12-03T13:49:35ZengTaylor & Francis GroupOncoImmunology2162-402X2024-12-0113110.1080/2162402X.2024.2363000β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancersSoumya Tumbath0Lingxiang Jiang1Xiaoguang Li2Taolan Zhang3Kashif Rafiq Zahid4Ye Zhao5Hao Zhou6Zhijun Yin7Tao Lu8Shu Jiang9Yaomin Chen10Xiang Chen11Yang-Xin Fu12Xiumei Huang13Department of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USADepartment of Pharmacology and Toxicology, Indiana University School of Medicine, Indianapolis, IN, USADivision of public health sciences, Washington University School of Medicine, St. Louis, MO, USAIndiana University Health Pathology Laboratory, Indiana University School of Medicine, Indianapolis, IN, USADepartment of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USADepartment of Pathology, University of Texas Southwestern Medical Center, Dallas, TX, USADepartment of Radiation Oncology, Indiana University School of Medicine, Indianapolis, IN, USANAD(P)H:quinone oxidoreductase 1 (NQO1) is overexpressed in most solid cancers, emerging as a promising target for tumor-selective killing. β-Lapachone (β-Lap), an NQO1 bioactivatable drug, exhibits significant antitumor effects on NQO1-positive cancer cells by inducing immunogenic cell death (ICD) and enhancing tumor immunogenicity. However, the interaction between β-Lap-mediated antitumor immune responses and neutrophils, novel antigen-presenting cells (APCs), remains unknown. This study demonstrates that β-Lap selectively kills NQO1-positive murine tumor cells by significantly increasing intracellular ROS formation and inducing DNA double strand breaks (DSBs), resulting in DNA damage. Treatment with β-Lap efficiently eradicates immunocompetent murine tumors and significantly increases the infiltration of tumor-associated neutrophils (TANs) into the tumor microenvironment (TME), which plays a crucial role in the drug’s therapeutic efficacy. Further, the presence of β-Lap-induced antigen medium leads bone marrow-derived neutrophils (BMNs) to directly kill murine tumor cells, aiding in dendritic cells (DCs) recruitment and significantly enhancing CD8+ T cell proliferation. β-Lap treatment also drives the polarization of TANs toward an antitumor N1 phenotype, characterized by elevated IFN-β expression and reduced TGF-β cytokine expression, along with increased CD95 and CD54 surface markers. β-Lap treatment also induces N1 TAN-mediated T cell cross-priming. The HMGB1/TLR4/MyD88 signaling cascade influences neutrophil infiltration into β-Lap-treated tumors. Blocking this cascade or depleting neutrophil infiltration abolishes the antigen-specific T cell response induced by β-Lap treatment. Overall, this study provides comprehensive insights into the role of tumor-infiltrating neutrophils in the β-Lap-induced antitumor activity against NQO1-positive murine tumors.https://www.tandfonline.com/doi/10.1080/2162402X.2024.2363000CD8+ T cellsneutrophil polarizationNQO1tumor infiltrated neutrophilsβ-Lapachone |
| spellingShingle | Soumya Tumbath Lingxiang Jiang Xiaoguang Li Taolan Zhang Kashif Rafiq Zahid Ye Zhao Hao Zhou Zhijun Yin Tao Lu Shu Jiang Yaomin Chen Xiang Chen Yang-Xin Fu Xiumei Huang β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers OncoImmunology CD8+ T cells neutrophil polarization NQO1 tumor infiltrated neutrophils β-Lapachone |
| title | β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers |
| title_full | β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers |
| title_fullStr | β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers |
| title_full_unstemmed | β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers |
| title_short | β-Lapachone promotes the recruitment and polarization of tumor-associated neutrophils (TANs) toward an antitumor (N1) phenotype in NQO1-positive cancers |
| title_sort | β lapachone promotes the recruitment and polarization of tumor associated neutrophils tans toward an antitumor n1 phenotype in nqo1 positive cancers |
| topic | CD8+ T cells neutrophil polarization NQO1 tumor infiltrated neutrophils β-Lapachone |
| url | https://www.tandfonline.com/doi/10.1080/2162402X.2024.2363000 |
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