Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma
Malignant peripheral nerve sheath tumors (MPNSTs) are a highly aggressive neoplasm of the peripheral nervous system and are resistant to most conventional cancer therapies. We previously showed that pretreatment with ruxolitinib (RUX) enhanced the efficacy of oncolytic herpes simplex virus (oHSV) vi...
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Elsevier
2025-03-01
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| Series: | Molecular Therapy: Oncology |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2950329924001711 |
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| author | Ravi Dhital Yeaseul Kim Doyeon Kim Ilse Hernandez-Aguirre Jack Hedberg Alexia Martin Kevin A. Cassady |
| author_facet | Ravi Dhital Yeaseul Kim Doyeon Kim Ilse Hernandez-Aguirre Jack Hedberg Alexia Martin Kevin A. Cassady |
| author_sort | Ravi Dhital |
| collection | DOAJ |
| description | Malignant peripheral nerve sheath tumors (MPNSTs) are a highly aggressive neoplasm of the peripheral nervous system and are resistant to most conventional cancer therapies. We previously showed that pretreatment with ruxolitinib (RUX) enhanced the efficacy of oncolytic herpes simplex virus (oHSV) virotherapy in this murine sarcoma model. A low abundance of tumor-infiltrating leukocytes and limitations in conventional flow cytometry restrict analyses to a narrow subset of immune cells, potentially introducing a confirmation bias. To address these limitations, we developed a 46-color spectral flow cytometry panel for the detailed analysis of immune cell dynamics following repeated oHSV dosing. Beyond the cytotoxic T lymphocyte (CTL) and regulatory T cell (Treg) changes reported in our earlier studies, RUX+oHSV treatment modulates myeloid and other lymphoid compartments, including germinal center B cell populations with enhanced activation. RUX+oHSV therapy also increased cytokine-expressing CD4(+) populations, predominantly granzyme B(+) cytotoxic-like, interferon (IFN)-γ(+) T helper type 1 (Th1)-like, and interleukin (IL)-21(+) T follicular helper (Tfh)-like phenotypes, within the tumor infiltrates, suggestive of potential tertiary lymphoid structure development in the treated tumors. Here, we illustrate the utility of a high-dimensional spectral flow cytometry panel that permits simultaneous evaluation of intratumoral CD4/CD8 T cell, Treg, γδ-T cell, natural killer T (NKT) cell, B cell, NK cell, monocyte, macrophage, granulocyte, myeloid-derived suppressor cell (MDSC), and dendritic cell functional changes from RUX+oHSV-treated MPNSTs. |
| format | Article |
| id | doaj-art-127ef8aadeec401c823fbca5429fae66 |
| institution | Kabale University |
| issn | 2950-3299 |
| language | English |
| publishDate | 2025-03-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Therapy: Oncology |
| spelling | doaj-art-127ef8aadeec401c823fbca5429fae662025-01-20T04:18:09ZengElsevierMolecular Therapy: Oncology2950-32992025-03-01331200929Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcomaRavi Dhital0Yeaseul Kim1Doyeon Kim2Ilse Hernandez-Aguirre3Jack Hedberg4Alexia Martin5Kevin A. Cassady6Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USACenter for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USACenter for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USACenter for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Biomedical Informatics, The Ohio State University College of Medicine, Columbus, OH, USACenter for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA; Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA; Department of Pediatrics, Division of Pediatric Infectious Diseases, Nationwide Children’s Hospital, Columbus, OH, USA; Corresponding author: Kevin A. Cassady, Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, USA.Malignant peripheral nerve sheath tumors (MPNSTs) are a highly aggressive neoplasm of the peripheral nervous system and are resistant to most conventional cancer therapies. We previously showed that pretreatment with ruxolitinib (RUX) enhanced the efficacy of oncolytic herpes simplex virus (oHSV) virotherapy in this murine sarcoma model. A low abundance of tumor-infiltrating leukocytes and limitations in conventional flow cytometry restrict analyses to a narrow subset of immune cells, potentially introducing a confirmation bias. To address these limitations, we developed a 46-color spectral flow cytometry panel for the detailed analysis of immune cell dynamics following repeated oHSV dosing. Beyond the cytotoxic T lymphocyte (CTL) and regulatory T cell (Treg) changes reported in our earlier studies, RUX+oHSV treatment modulates myeloid and other lymphoid compartments, including germinal center B cell populations with enhanced activation. RUX+oHSV therapy also increased cytokine-expressing CD4(+) populations, predominantly granzyme B(+) cytotoxic-like, interferon (IFN)-γ(+) T helper type 1 (Th1)-like, and interleukin (IL)-21(+) T follicular helper (Tfh)-like phenotypes, within the tumor infiltrates, suggestive of potential tertiary lymphoid structure development in the treated tumors. Here, we illustrate the utility of a high-dimensional spectral flow cytometry panel that permits simultaneous evaluation of intratumoral CD4/CD8 T cell, Treg, γδ-T cell, natural killer T (NKT) cell, B cell, NK cell, monocyte, macrophage, granulocyte, myeloid-derived suppressor cell (MDSC), and dendritic cell functional changes from RUX+oHSV-treated MPNSTs.http://www.sciencedirect.com/science/article/pii/S2950329924001711MPNSTruxolitiniboncolytic HSVspectral flow cytometrycytotoxic CD4(+) T cellsgerminal center B cells |
| spellingShingle | Ravi Dhital Yeaseul Kim Doyeon Kim Ilse Hernandez-Aguirre Jack Hedberg Alexia Martin Kevin A. Cassady Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma Molecular Therapy: Oncology MPNST ruxolitinib oncolytic HSV spectral flow cytometry cytotoxic CD4(+) T cells germinal center B cells |
| title | Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma |
| title_full | Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma |
| title_fullStr | Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma |
| title_full_unstemmed | Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma |
| title_short | Ruxolitinib and oHSV combination therapy increases CD4 T cell activity and germinal center B cell populations in murine sarcoma |
| title_sort | ruxolitinib and ohsv combination therapy increases cd4 t cell activity and germinal center b cell populations in murine sarcoma |
| topic | MPNST ruxolitinib oncolytic HSV spectral flow cytometry cytotoxic CD4(+) T cells germinal center B cells |
| url | http://www.sciencedirect.com/science/article/pii/S2950329924001711 |
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