Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors.

Autor:	Paudel SN; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Hutzen BJ; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Miller KE; Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States., Garfinkle EAR; Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Chen CY; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Wang PY; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Glaspell AM; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Currier MA; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Ringwalt EM; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States., Boon L; JJP Biologics, Warsaw, Poland., Mardis ER; Institute for Genomic Medicine, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States., Cairo MS; Department of Pediatrics, Medicine, Pathology, Microbiology and Immunology, and Cell Biology, New York Medical College, Valhalla, NY, United States., Ratner N; Cancer and Blood Diseases Institute, Cincinnati Children's Hospital Medical Center, Cincinnati, OH, United States., Dodd RD; Department of Internal Medicine, Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, United States., Cassady KA; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States., Cripe TP; Center for Childhood Cancer Research, The Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, OH, United States.; Department of Pediatrics, The Ohio State University Wexner College of Medicine, Columbus, OH, United States.; Division of Pediatric Hematology/Oncology/BMT, Nationwide Children's Hospital, Columbus, OH, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2024 Jun 25; Vol. 15, pp. 1384623. Date of Electronic Publication: 2024 Jun 25 (Print Publication: 2024).
DOI:	10.3389/fimmu.2024.1384623
Abstrakt:	Introduction: Malignant peripheral nerve sheath tumors (MPNST) pose a significant therapeutic challenge due to high recurrence rates after surgical resection and a largely ineffective response to traditional chemotherapy. An alternative treatment strategy is oncolytic viroimmunotherapy, which can elicit a durable and systemic antitumor immune response and is Food and Drug Administration (FDA)-approved for the treatment of melanoma. Unfortunately, only a subset of patients responds completely, underscoring the need to address barriers hindering viroimmunotherapy effectiveness. Methods: Here we investigated the therapeutic utility of targeting key components of the MPNST immunosuppressive microenvironment to enhance viroimmunotherapy's antitumor efficacy in three murine models, one of which showed more immunogenic characteristics than the others. Results: Myelomodulatory therapy with pexidartinib, a small molecule inhibitor of CSF1R tyrosine kinase, and the oncolytic herpes simplex virus T-VEC exhibited the most significant increase in median survival time in the highly immunogenic model. Additionally, targeting myeloid cells with the myelomodulatory therapy trabectedin, a small molecule activator of caspase-8 dependent apoptosis, augmented the survival benefit of T-VEC in a less immunogenic MPNST model. However, tumor regressions or shrinkages were not observed. Depletion experiments confirmed that the enhanced survival benefit relied on a T cell response. Furthermore, flow cytometry analysis following combination viroimmunotherapy revealed decreased M2 macrophages and myeloid-derived suppressor cells and increased tumor-specific gp70+ CD8 T cells within the tumor microenvironment. Discussion: In summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation. Competing Interests: LB was employed by JJP Biologics. MSC has served as a consultant for Jazz Pharmaceuticals, Omeros Pharmaceuticals, Servier Pharmaceuticals, Abbvie and Novartis Pharmaceuticals; Speakers Bureau for Jazz Pharmaceuticals, Amgen, Inc., Sanofi and Sobi; Advisory Board for Astra Zeneca; and research funding from Celularity, Merck, Miltenyi Biotec, Servier, Omeros, Jazz and Janssen. KC holds intellectual property for oncolytic virus C134, which was licensed to Mustang Bio. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision. (Copyright © 2024 Paudel, Hutzen, Miller, Garfinkle, Chen, Wang, Glaspell, Currier, Ringwalt, Boon, Mardis, Cairo, Ratner, Dodd, Cassady and Cripe.)
Databáze:	MEDLINE
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