Liu et al. analyzed IFN-stimulated gene (ISG) signatures in TCGA tumors and patient-derived tumor xenografts, and found that some tumor cells constitutively produced IFN via a STING-dependent pathway. The chronic ISG state rendered tumor cells sensitive to loss of ADAR (an IFN-inducible enzyme that converts adenosine to inosine and prevents sensing of double-stranded RNA [dsRNA]) and upregulated dsRNA sensors PKR and MAVS. In the presence of unedited dsRNA, activated PKR led to enhanced IFN production, while MAVS amplified the ISGs. In the context of chronic ISG, ADAR loss reduced tumor growth in vitro and in vivo.
Interferons (IFNs) are cytokines that play a critical role in limiting infectious and malignant diseases (1-4) . Emerging data suggest that the strength and duration of IFN signaling can differentially impact cancer therapies, including immune checkpoint blockade (5-7) . Here, we characterize the output of IFN signaling, specifically IFN-stimulated gene (ISG) signatures, in primary tumors from The Cancer Genome Atlas. While immune infiltration correlates with the ISG signature in some primary tumors, the existence of ISG signature-positive tumors without evident infiltration of IFN-producing immune cells suggests that cancer cells per se can be a source of IFN production. Consistent with this hypothesis, analysis of patient-derived tumor xenografts propagated in immune-deficient mice shows evidence of ISG-positive tumors that correlates with expression of human type I and III IFNs derived from the cancer cells. Mechanistic studies using cell line models from the Cancer Cell Line Encyclopedia that harbor ISG signatures demonstrate that this is a by-product of a STING-dependent pathway resulting in chronic tumor-derived IFN production. This imposes a transcriptional state on the tumor, poising it to respond to the aberrant accumulation of double-stranded RNA (dsRNA) due to increased sensor levels (MDA5, RIG-I and PKR). By interrogating our functional short-hairpin RNA screen dataset across 398 cancer cell lines, we show that this ISG transcriptional state creates a novel genetic vulnerability. ISG signature-positive cancer cells are sensitive to the loss of ADAR, a dsRNA-editing enzyme that is also an ISG. A genome-wide CRISPR genetic suppressor screen reveals that the entire type I IFN pathway and the dsRNA-activated kinase, PKR, are required for the lethality induced by ADAR depletion. Therefore, tumor-derived IFN resulting in chronic signaling creates a cellular state primed to respond to dsRNA accumulation, rendering ISG-positive tumors susceptible to ADAR loss.
Author Info: (1) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (2) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, U
Author Info: (1) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (2) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (3) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (4) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (5) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (6) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (7) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (8) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (9) Novartis Institutes for Biomedical Research, Oncology Disease Area, Basel, Switzerland. (10) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (11) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (12) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (13) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (14) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (15) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (16) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (17) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (18) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. (19) Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. rob.mcdonald@novartis.com.
