| Autor: |
Liu H; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Golji J; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Brodeur LK; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Chung FS; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Chen JT; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., deBeaumont RS; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Bullock CP; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Jones MD; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Kerr G; Novartis Institutes for Biomedical Research, Oncology Disease Area, Basel, Switzerland., Li L; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Rakiec DP; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Schlabach MR; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Sovath S; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Growney JD; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Pagliarini RA; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Ruddy DA; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., MacIsaac KD; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., Korn JM; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA., McDonald ER 3rd; Novartis Institutes for Biomedical Research, Oncology Disease Area, Cambridge, MA, USA. rob.mcdonald@novartis.com. |
| Abstrakt: |
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. |
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