Endogenous retrovirus envelope as a tumor-associated immunotherapeutic target in murine osteosarcoma

Wedekind, Mary Frances; Miller, Katherine E.; Chen, Chun-Yu; Wang, Pin-Yi; Hutzen, Brian; Currier, Mark A.; Nartker, Brooke; Roberts, Ryan D.; Boon, Louis; Conner, Joe; LaHaye, Stephanie; Kelly, Benjamin J.; Gordon, David; White, Peter; Mardis, Elaine R.; Cripe, Timothy P.

doi:10.1016/j.isci.2021.102759

Cited by 3 publications

(2 citation statements)

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“…BALB/c Murine Leukemia Virus GP70 biotinylated monomer (H2-Ld-SPSYVYHQF) was obtained from the NIH tetramer core facility. This monomer was then tetramerized using streptavidin-APC to generate APC-conjugated GP70 as previously described ( 24 ). For Foxp3 intracellular staining, mononuclear cells were enriched by Percoll density gradient centrifugation (GE Healthcare Bio-Sciences, Pittsburgh, PA, USA).…”

Section: Methodsmentioning

confidence: 99%

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

Paudel,

Hutzen,

Miller

et al. 2024

Front. Immunol.

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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.

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Section: Methodsmentioning

confidence: 99%

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

Paudel,

Hutzen,

Miller

et al. 2024

Front. Immunol.

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“…An H-2Ld-restricted MuLV gp70-APC tetramer (MBL International, Woburn, MA) was used to identify tumor-specific CD8 + T cells, as K7M2 cells have been shown to express the gp70 protein. 63 All samples were acquired on a CytoFLEX flow cytometer (Beckman Coulter, Brea, CA) with FACSDiva software (BD Biosciences, Franklin Lakes, NJ). Data analyses were performed using FlowJo v.10 (FlowJo, Ashland, OR) and SPICE software.…”

Section: Methodsmentioning

confidence: 99%

Galectin-3 inhibition boosts the therapeutic efficacy of Semliki Forest virus in pediatric osteosarcoma

Herrador

Zalacaín

Labiano

et al. 2022

Molecular Therapy - Oncolytics

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Oncolytic Viral Therapy in Osteosarcoma

Karadimas,

Huynh,

Chose

et al. 2024

Viruses

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Primary bone malignancies, including osteosarcoma (OS), are rare but aggressive. Current OS treatment, involving surgical resection and chemotherapy, has improved survival for non-metastatic cases but remains ineffective for recurrent or metastatic OS. Oncolytic viral therapy (OVT) is a promising alternative, using naturally occurring or genetically modified viruses to selectively target and lyse cancer cells and induce a robust immune response against remaining OS cells. Various oncolytic viruses (OVs), such as adenovirus, herpes simplex virus, and measles virus, have demonstrated efficacy in preclinical OS models. Combining OVT with other therapeutics, such as chemotherapy or immunotherapy, may further improve outcomes. Despite these advances, challenges in reliability of preclinical models, safety, delivery, and immune response must be addressed to optimize OVT for clinical use. Future research should focus on refining delivery methods, exploring combination treatments, and clinical trials to ensure OVT’s efficacy and safety for OS. Overall, OVT represents a novel approach with the potential to drastically improve survival outcomes for patients with OS.

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Endogenous retrovirus envelope as a tumor-associated immunotherapeutic target in murine osteosarcoma

Abstract: HighlightsK7M2 but not F420 responds to viroimmunotherapy K7M2 and F420 exhibit similar tumor mutational burdens K7M2 shows much higher expression of endogenous retrovirus genes including gp70 Tetramer staining suggest gp70 is the immune target in K7M2

Cited by 3 publications

References 60 publications

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

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

Galectin-3 inhibition boosts the therapeutic efficacy of Semliki Forest virus in pediatric osteosarcoma

Oncolytic Viral Therapy in Osteosarcoma

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