Integrity of the Antiviral STING-mediated DNA Sensing in Tumor Cells Is Required to Sustain the Immunotherapeutic Efficacy of Herpes Simplex Oncolytic Virus

Abstract

The dichotomic contribution of cancer cell lysis and tumor immunogenicity is considered essential for effective oncovirotherapy, suggesting that the innate antiviral immune response is a hurdle for efficacy of oncolytic viruses. However, emerging evidence is resizing this view. By sensing cytosolic DNA, the cyclic GMP-AMP synthase (cGAS) and stimulator of interferon genes (STING) axis can both counteract viral spread and contribute to the elicitation of adaptive immunity via type I interferon responses. In this paper, we analyzed the tumor-resident function of Sting-mediated DNA sensing in a combined approach of oncovirotherapy and PD-1 immune checkpoint blockade, in an immunocompetent murine model. While supporting increased lytic potential by oncolytic HER2-retargeted HSV-1 in vitro and in vivo, Sting-knockout tumors showed molecular signatures of an immunosuppressive tumor microenvironment. These signatures were correspondingly associated with ineffectiveness of the combination therapy in a model of established tumors. Results suggest that the impairment in antiviral response of Sting-knockout tumors, while favoring viral replication, is not able to elicit an adequate immunotherapeutic effect, due to lack of immunogenic cell death and the inability of Sting-knockout cancer cells to promote anti-tumor adaptive immune responses. Accordingly, we propose that antiviral, tumor-resident Sting provides fundamental contributions to immunotherapeutic efficacy of oncolytic viruses.

Generation of a Novel Mesothelin-Targeted Oncolytic Herpes Virus and Implemented Strategies for Manufacturing

“…The conservation of these escape mechanisms across different viruses underlines the key role that STING gene plays in host and microbe interactions [ 79 , 80 ]. We have recently described how the DNA sensing regulator STING is crucial to restrict the replication of an oncolytic HER2-retargeted Herpes virus [ 47 ]. Based on this evidence, we speculated that the functional inactivation of STING in a suitable producing cell line could improve the yield of oncolytic vectors, including retargeted THV_SS1.…”

“…The use of viral vectors for gene therapy, vaccine delivery, and oncolytic viruses is now a reality, with thousands of clinical trials completed, ongoing, or approved worldwide [ 1 , 3 , 82 , 83 ]. Oncovirotherapy with retargeted viruses is revealing a promising potential for the treatment of many cancer indicators, including breast cancer [ 7 , 23 , 47 , 66 , 84 ]. We recently characterized preclinical models of HER2-positive tumors in the framework of combination with checkpoint inhibitors [ 7 , 23 , 47 ].…”

“…Oncovirotherapy with retargeted viruses is revealing a promising potential for the treatment of many cancer indicators, including breast cancer [ 7 , 23 , 47 , 66 , 84 ]. We recently characterized preclinical models of HER2-positive tumors in the framework of combination with checkpoint inhibitors [ 7 , 23 , 47 ]. Among breast cancer, triple-negative tumors are characterized by lack of canonical breast receptors (i.e., HER2, ER, PR) amenable by targeted therapeutics.…”

“…Thus, the implementation of an efficient virus manufacturing strategy is desirable. We recently demonstrated that the genetic material of viruses is probably the main pathogen associated molecular pattern (PAMP) recognized by intracellular Pattern Recognition Receptors (PRR) [ 47 ]. Interestingly, beyond toll-like receptors (TLRs) expressed by specialized immune cells, emerging evidence is revealing novel constitutive PRR genes widely expressed in all tissues and organs.…”

Personalizing Oncolytic Virotherapy for Glioblastoma: In Search of Biomarkers for Response

“…For instance, it has been shown that STING pathway is correlated with oncolytic herpes virus-1 resistance (see below). However, new evidence shows that this advantage in viral replication may not correlate with tumor eradication in vivo [ 77 ]. This may be explained by the inability of oncolytic viruses to induce immunogenic cell death in STING-deficient tumor cells, thus hampering the induction of innate and adaptive immunity [ 78 ].…”