Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models

Deepa Seetharam, Department of Neurosurgery and.
Jay Chandar, Department of Neurosurgery and.
Christian K. Ramsoomair, Department of Neurosurgery and.
Jelisah F. Desgraves, Department of Neurosurgery and.
Alexandra Alvarado Medina, Department of Neurosurgery and.
Anna Jane Hudson, Department of Neurosurgery and.
Ava Amidei, Department of Neurosurgery and.
Jesus R. Castro, Department of Neurosurgery and.
Vaidya Govindarajan, Department of Neurosurgery and.
Sarah Wang, Department of Neurosurgery and.
Yong Zhang, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Adam M. Sonabend, Department of Neurological Surgery and.
Mynor J. Mendez Valdez, Department of Neurosurgery and.
Dragan Maric, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Vasundara Govindarajan, Department of Neurosurgery and.
Sarah R. Rivas, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Victor M. Lu, Department of Neurosurgery and.
Ritika Tiwari, Desai Sethi Urology Institute University of Miami, Miller School of Medicine, Miami, Florida, USA.
Nima Sharifi, Desai Sethi Urology Institute University of Miami, Miller School of Medicine, Miami, Florida, USA.
Emmanuel Thomas, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Marcus Alexander, Department of Neurosurgery and.
Catherine DeMarino, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Kory Johnson, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
Macarena I. De La Fuente, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Ruham Alshiekh Nasany, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Teresa Maria Noviello, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Michael E. Ivan, Department of Neurosurgery and.
Ricardo J. Komotar, Department of Neurosurgery and.
Antonio Iavarone, Department of Neurosurgery and.
Avindra Nath, National Institute of Neurological Disorders and Stroke, NIH, Bethesda, Maryland, USA.
John Heiss, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.
Michele Ceccarelli, Sylvester Comprehensive Cancer Center, University of Miami, Miller School of Medicine, Miami, Florida, USA.

Document Type

Journal Article

Publication Date

3-17-2025

Journal

The Journal of clinical investigation

Volume

135

Issue

6

DOI

10.1172/JCI183745

Keywords

Brain cancer; Cancer immunotherapy; Epigenetics; Oncology; Virology

Abstract

Viral mimicry refers to the activation of innate antiviral immune responses due to the induction of endogenous retroelements (REs). Viral mimicry augments antitumor immune responses and sensitizes solid tumors to immunotherapy. Here, we found that targeting what we believe to be a novel, master epigenetic regulator, Zinc Finger Protein 638 (ZNF638), induces viral mimicry in glioblastoma (GBM) preclinical models and potentiates immune checkpoint inhibition (ICI). ZNF638 recruits the HUSH complex, which precipitates repressive H3K9me3 marks on endogenous REs. In GBM, ZNF638 is associated with marked locoregional immunosuppressive transcriptional signatures, reduced endogenous RE expression, and poor immune cell infiltration. Targeting ZNF638 decreased H3K9 trimethylation, increased REs, and activated intracellular dsRNA signaling cascades. Furthermore, ZNF638 knockdown upregulated antiviral immune programs and significantly increased PD-L1 immune checkpoint expression in diverse GBM models. Importantly, targeting ZNF638 sensitized mice to ICI in syngeneic murine orthotopic models through innate IFN signaling. This response was recapitulated in recurrent GBM (rGBM) samples with radiographic responses to checkpoint inhibition with widely increased expression of dsRNA, PD-L1, and perivascular CD8 cell infiltration, suggesting that dsRNA signaling may mediate response to immunotherapy. Finally, low ZNF638 expression was a biomarker of clinical response to ICI and improved survival in patients with rGBM and patients with melanoma. Our findings suggest that ZNF638 could serve as a target to potentiate immunotherapy in gliomas.

Department

Microbiology, Immunology, and Tropical Medicine

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