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Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus
Warren Floyd, … , Diana M. Cardona, David G. Kirsch
Warren Floyd, … , Diana M. Cardona, David G. Kirsch
Published May 18, 2023
Citation Information: J Clin Invest. 2023;133(13):e149310. https://doi.org/10.1172/JCI149310.
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Research Article Oncology Article has an altmetric score of 17

Atrx deletion impairs CGAS/STING signaling and increases sarcoma response to radiation and oncolytic herpesvirus

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Abstract

ATRX is one of the most frequently altered genes in solid tumors, and mutation is especially frequent in soft tissue sarcomas. However, the role of ATRX in tumor development and response to cancer therapies remains poorly understood. Here, we developed a primary mouse model of soft tissue sarcoma and showed that Atrx-deleted tumors were more sensitive to radiation therapy and to oncolytic herpesvirus. In the absence of Atrx, irradiated sarcomas had increased persistent DNA damage, telomere dysfunction, and mitotic catastrophe. Our work also showed that Atrx deletion resulted in downregulation of the CGAS/STING signaling pathway at multiple points in the pathway and was not driven by mutations or transcriptional downregulation of the CGAS/STING pathway components. We found that both human and mouse models of Atrx-deleted sarcoma had a reduced adaptive immune response, markedly impaired CGAS/STING signaling, and increased sensitivity to TVEC, an oncolytic herpesvirus that is currently FDA approved for the treatment of aggressive melanomas. Translation of these results to patients with ATRX-mutant cancers could enable genomically guided cancer therapy approaches to improve patient outcomes.

Authors

Warren Floyd, Matthew Pierpoint, Chang Su, Rutulkumar Patel, Lixia Luo, Katherine Deland, Amy J. Wisdom, Daniel Zhu, Yan Ma, Suzanne Bartholf DeWitt, Nerissa T. Williams, Alexander L. Lazarides, Jason A. Somarelli, David L. Corcoran, William C. Eward, Diana M. Cardona, David G. Kirsch

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Figure 8

Atrx deletion increases sarcoma sensitivity to oncolytic herpesvirus therapy.

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Atrx deletion increases sarcoma sensitivity to oncolytic herpesvirus the...
(A) Diagram showing the interaction between oncolytic herpesvirus and CGAS/STING pathway in Atrx WT sarcoma cells. Oncolytic herpes virus dsDNA is detected and CGAS/STING signaling activates the innate immune response, which inhibits viral spread and oncolytic herpesvirus efficacy. (B) RT-PCR of Ifnb1 for Atrx WT and Atrx KO isogenic sarcoma cell lines (n = 3) assayed 24 hours after treatment with HSV-60, a 60-bp dsDNA oligonucleotide derived from HSV-1 that is a known inducer of CGAS/STING signaling. For statistical analysis, a ratio paired t test was performed, pairing each Atrx KO cell line to its Atrx WT isogenic cell line counterpart. (C) IC50 assays for isogenic mouse sarcoma cell lines (n = 3) treated with oncolytic herpesvirus (oHSV) ordered from Imanis Life Sciences. Differences between all paired cell lines are statistically significant (P <.05) as analyzed by a ratio paired t test. Each data point represents a biological replicate. (D) IC50 assays for the 143B human Sarcoma cell line with or without ATRX deletion, as well as the U2OS human sarcoma cell line, which is lacks protein expression of both ATRX and STING. Each dot represents a separate experimental replicate of the IC50 assay (n = 3 per cell line). Statistical analysis was performed using multiple Welch’s t tests corrected for multiple comparisons using the Holm-Šídák method. (E) Measurement of P7 KP (n = 21) and P7KPA (n = 12) tumor growth after treatment with a mouse optimized version of TVEC oncolytic herpesvirus, as measured by time for tumor to quintuple in size relative to size at treatment. Comparison of survival curves was performed using log-rank (Mantel Cox) test. (F) Measurement of P7 KP (n = 31) and P7 KPA (n = 23) tumor growth rates after 20 Gy hindlimb irradiation followed by treatment with a mouse optimized TVEC oncolytic herpesvirus, as measured by time for tumor to quintuple in size relative to size at treatment. Comparison of survival curves was performed using log-rank (Mantel Cox) test.

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