Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models
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.
Authors
- Avindra Nath (ORCID: https://orcid.org/0000-0003-0927-5855)
- Mynor J. Mendez Valdez (ORCID: https://orcid.org/0000-0001-7899-0751)
- Ritika Tiwari (ORCID: https://orcid.org/0000-0002-9896-366X)
- María E. Figueroa (ORCID: https://orcid.org/0000-0003-4887-4981)
- Abelardo Medina (ORCID: https://orcid.org/0000-0002-4042-2190)
- Christian Ramsoomair
- Emmanuel Thomas (ORCID: https://orcid.org/0000-0003-1416-3903)
- Kory Johnson (ORCID: https://orcid.org/0000-0001-7678-3812)
- Sarah Rivas
- Nima Sharifi (ORCID: https://orcid.org/0000-0003-1281-3474)
- Katherine B. Chiappinelli (ORCID: https://orcid.org/0000-0001-9241-9105)
- Teresa Noviello (ORCID: https://orcid.org/0000-0002-3411-6752)
- Defne Bayık (ORCID: https://orcid.org/0000-0002-4740-8869)
- Victor M. Lu (ORCID: https://orcid.org/0000-0002-9470-5890)
- Ashish H. Shah (ORCID: https://orcid.org/0000-0002-0183-1274)
- Vaidya Govindarajan (ORCID: https://orcid.org/0000-0002-0248-346X)
- Macarena I. de la Fuente
- John D. Heiss (ORCID: https://orcid.org/0000-0002-3890-0165)
- Adam M. Sonabend (ORCID: https://orcid.org/0000-0002-8347-1945)
- Michael E. Ivan (ORCID: https://orcid.org/0000-0002-4798-4989)
- Jay Chandar (ORCID: https://orcid.org/0000-0001-5923-3579)
- Antonio Iavarone (ORCID: https://orcid.org/0000-0002-0683-4634)
- Ruham Alshiekh Nasany (ORCID: https://orcid.org/0000-0001-6600-3181)
- Dragan Maric (ORCID: https://orcid.org/0000-0003-2912-7921)
- Marcus Alexander (ORCID: https://orcid.org/0000-0001-8627-7534)
- Michele Ceccarelli (ORCID: https://orcid.org/0000-0002-4702-6617)
- Anna Hudson (ORCID: https://orcid.org/0000-0002-5668-6668)
- Deepa Seetharam (ORCID: https://orcid.org/0000-0002-4886-5025)
- Catherine DeMarino (ORCID: https://orcid.org/0000-0002-3608-5451)
- Jelisah Desgraves
- Yong Zhang (ORCID: https://orcid.org/0000-0001-9950-1793)
- Sarah Wang (ORCID: https://orcid.org/0000-0001-8819-6447)
- Venkatesh Govindarajan (ORCID: https://orcid.org/0000-0003-2016-9105)
- Jesús Castro
- Ricardo J. Komotar
- Ava Amidei (ORCID: https://orcid.org/0009-0000-2966-6218)
Institutions
- Northwestern University (US)
- University of Miami (US)
- George Washington University (US)
- National Institute of Neurological Disorders and Stroke (US)
- Northwestern Medicine (US)
- Miami Transplant Institute (US)
- Sylvester Comprehensive Cancer Center (US)
Publication Details
- Journal
- Journal of Clinical Investigation
- Published
- 2025-03-16
- DOI
- https://doi.org/10.1172/jci183745
- Citations
- 6
- Primary Topic
- interferon and immune responses
- Type
- article
- Field-Weighted Citation Impact
- 4.78
Funders
- Elsa U. Pardee Foundation
- Neurosurgery Research and Education Foundation
- National Institutes of Health