Journal article
Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors
Frontiers in immunology, Vol.15, 1384623
06/01/2024
DOI: 10.3389/fimmu.2024.1384623
PMCID: PMC11263800
PMID: 39044819
Abstract
IntroductionMalignant 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. MethodsHere 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. ResultsMyelomodulatory 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. DiscussionIn summary, our findings provide compelling evidence for the potential to leverage viroimmunotherapy with myeloid cell targeting against MPNST and warrant further investigation.
Details
- Title: Subtitle
- Myelomodulatory treatments augment the therapeutic benefit of oncolytic viroimmunotherapy in murine models of malignant peripheral nerve sheath tumors
- Creators
- Siddhi N. Paudel - Nationwide Children's HospitalBrian J. Hutzen - Nationwide Children's HospitalKatherine E. Miller - Nationwide Children's HospitalElizabeth A. R. Garfinkle - Nationwide Children's HospitalChun-Yu Chen - Nationwide Children's HospitalPin-Yi Wang - Nationwide Children's HospitalAndrea M. Glaspell - Nationwide Children's HospitalMark A. Currier - Nationwide Children's HospitalEmily M. Ringwalt - Nationwide Children's HospitalLouis Boon - JJP Biologics, Warsaw, PolandElaine R. Mardis - Nationwide Children's HospitalMitchell S. Cairo - New York Medical CollegeNancy Ratner - Cincinnati Children's Hospital Medical CenterRebecca D. Dodd - University of IowaKevin A. Cassady - The Ohio State University Wexner Medical CenterTimothy P. Cripe - The Ohio State University Wexner Medical Center
- Resource Type
- Journal article
- Publication Details
- Frontiers in immunology, Vol.15, 1384623
- Publisher
- Frontiers Media S.A
- DOI
- 10.3389/fimmu.2024.1384623
- PMID
- 39044819
- PMCID
- PMC11263800
- eISSN
- 1664-3224
- Language
- English
- Date published
- 06/01/2024
- Academic Unit
- Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
- Record Identifier
- 9984648353202771
Metrics
3 Record Views