Arming oHSV with ULBP3 drives abscopal immunity in lymphocyte-depleted glioblastoma.
- Wirsching HG Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Zhang H Clinical Research Division and.
- Szulzewsky F Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Arora S Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Grandi P Department of Microbiology and Molecular Genetics and.
- Cimino PJ Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Amankulor N Department of Neurosurgery, School of Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania, USA.
- Campbell JS Clinical Research Division and.
- McFerrin L Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Pattwell SS Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Ene C Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Hicks A Oncorus, Cambridge, Massachusetts, USA.
- Ball M Oncorus, Cambridge, Massachusetts, USA.
- Yan J Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Zhang J Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Kumasaka D Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- Pierce RH Clinical Research Division and.
- Weller M Department of Neurology and Brain Tumor Center, University Hospital Zurich and University of Zurich, Zurich, Switzerland.
- Finer M Oncorus, Cambridge, Massachusetts, USA.
- Quéva C Oncorus, Cambridge, Massachusetts, USA.
- Glorioso JC Department of Microbiology and Molecular Genetics and.
- Houghton AM Clinical Research Division and.
- Holland EC Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
- 2019-07-12
Published in:
- JCI insight. - 2019
Brain cancer
Oncology
Animals
Antigen Presentation
Antineoplastic Agents, Immunological
Brain
Brain Neoplasms
Cell Line, Tumor
Combined Modality Therapy
Disease Models, Animal
Female
GPI-Linked Proteins
Gene Expression Regulation, Neoplastic
Glioblastoma
Humans
Intercellular Signaling Peptides and Proteins
Isocitrate Dehydrogenase
Kaplan-Meier Estimate
Male
Mice
Mice, Transgenic
Oncolytic Virotherapy
Oncolytic Viruses
Primary Cell Culture
Programmed Cell Death 1 Receptor
Recombinant Proteins
Simplexvirus
Up-Regulation
English
Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSVULBP3 with anti-programmed cell death 1 (anti-PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti-PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti-PD-1-sensitive abscopal effect of oHSVULBP3 warrants further investigation in patients with IDH wild-type glioblastoma.
- Language
-
- English
- Open access status
- gold
- Identifiers
-
- DOI 10.1172/jci.insight.128217
- PMID 31292299
- Persistent URL
- https://sonar.ch/global/documents/11849
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