Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models
Deepa Seetharam, Jay Chandar, Christian K. Ramsoomair, Jelisah F. Desgraves, Alexandra Alvarado Medina, Anna Jane Hudson, Ava Amidei, Jesus R. Castro, Vaidya Govindarajan, Sarah Wang, Yong Zhang, Adam M. Sonabend, Mynor J. Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah R. Rivas, Victor M. Lu, Ritika Tiwari, Nima Sharifi, Emmanuel Thomas, Marcus Alexander, Catherine DeMarino, Kory Johnson, Macarena I. De La Fuente, Ruham Alshiekh Nasany, Teresa Maria Rosaria Noviello, Michael E. Ivan, Ricardo J. Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine B. Chiappinelli, Maria E. Figueroa, Defne Bayik, Ashish H. Shah
Deepa Seetharam, Jay Chandar, Christian K. Ramsoomair, Jelisah F. Desgraves, Alexandra Alvarado Medina, Anna Jane Hudson, Ava Amidei, Jesus R. Castro, Vaidya Govindarajan, Sarah Wang, Yong Zhang, Adam M. Sonabend, Mynor J. Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah R. Rivas, Victor M. Lu, Ritika Tiwari, Nima Sharifi, Emmanuel Thomas, Marcus Alexander, Catherine DeMarino, Kory Johnson, Macarena I. De La Fuente, Ruham Alshiekh Nasany, Teresa Maria Rosaria Noviello, Michael E. Ivan, Ricardo J. Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine B. Chiappinelli, Maria E. Figueroa, Defne Bayik, Ashish H. Shah
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Research Article Oncology Virology

Activating antiviral immune responses potentiates immune checkpoint inhibition in glioblastoma models

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.

Authors

Deepa Seetharam, Jay Chandar, Christian K. Ramsoomair, Jelisah F. Desgraves, Alexandra Alvarado Medina, Anna Jane Hudson, Ava Amidei, Jesus R. Castro, Vaidya Govindarajan, Sarah Wang, Yong Zhang, Adam M. Sonabend, Mynor J. Mendez Valdez, Dragan Maric, Vasundara Govindarajan, Sarah R. Rivas, Victor M. Lu, Ritika Tiwari, Nima Sharifi, Emmanuel Thomas, Marcus Alexander, Catherine DeMarino, Kory Johnson, Macarena I. De La Fuente, Ruham Alshiekh Nasany, Teresa Maria Rosaria Noviello, Michael E. Ivan, Ricardo J. Komotar, Antonio Iavarone, Avindra Nath, John Heiss, Michele Ceccarelli, Katherine B. Chiappinelli, Maria E. Figueroa, Defne Bayik, Ashish H. Shah

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Figure 3

ZNF638 suppresses total RE expression and dsRNA sensing.

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ZNF638 suppresses total RE expression and dsRNA sensing. (A) Single-cell...
(A) Single-cell RNA-seq and clustered analysis depicting ZNF638 expression and Neftel state classification (n = 18,400 cells) (NPC-like, neural-progenitor-like; OPC-like, oligodendrocyte-progenitor-like; AC-like, astrocyte-like; MES-like, mesenchymal-like). (B) Heatmap depicting reduced cellular expression of the retroviral silencing complex (ZNF638, SETDB1, PPHLN1, MPHOSPH8, TASOR) is associated with increased total retroelement expression and increased expression of genes involved in the dsRNA sensing pathway (RIG-I, IFIH1, TLR3, IRF3, IRF7, MAVS) (n = 18,400 cells, REs = 5,680). (C) Low ZNF638 expression is associated with increased lymphocyte expression in individual GBM tumors using unsupervised clustering. UMAPs from tumors with low (ntumors = 4, ncells = 17,535) and high (ntumors = 4, ncells = 20,517) ZNF638 expression show heterogenous and distinct enrichment of cell types. (D) Violin plots illustrate the expression levels of B cells, dendritic cells, differentiated-like cells, endothelial cells, fibroblasts, granulocytes, myeloid cells, oligodendrocytes, pericytes, proliferative stem-like cells, stem-like cells, and T cells in tumors with low versus high ZNF638 expression, based on unbiased cell type annotation. While a trend toward increased infiltration of T cells, B cells, myeloid cells, and oligodendrocytes is observed, this did not reach statistical significance, likely due to the limited number of samples. Single-cell data for panels A–D were obtained from the European Genome-Phenome Archive under accession number EGAS00001005300.