Biomarker-driven and gene-enhanced viral therapy for malignant peripheral nerve sheath tumor
Listed in
This article is not in any list yet, why not save it to one of your lists.Abstract
Background
High-grade malignant peripheral nerve sheath tumors (MPNST) frequently lose Polycomb Repressive Complex 2 (PRC2), reducing the repressive histone mark, H3K27me3. We hypothesized that H3K27me3 loss sensitizes MPNST to oncolytic HSV due to impaired transcriptional resistance. HSV replication is also restricted by the integrated stress response, normally countered by HSV ICP34.5, representing an additional resistance pathway to ICP34.5 -attenuated HSV.
Methods
PRC2 loss-of-function was evaluated as a biomarker of HSV G47Δ ( ΔICP34.5 ) susceptibility in MPNST using isogenic, pharmacologic inhibition, and genetic rescue models. CUT&RUN and RNA-sequencing defined PRC2-dependent viral and host responses. We engineered a G47Δ-derived vector (G47Δ 2 ) with tumor-regulated ICP34.5 expression [G47Δ 2 ,ins( BIRC5>ICP34.5 )] and evaluated efficacy in MPNST xenografts.
Results
H3K27me3 deficiency increased G47Δ sensitivity and viral spread in vitro . CUT&RUN demonstrated PRC2-dependent H3K27me3 accumulation on the viral genome, explaining G47Δ activity in H3K27me3-deficient MPNST. RNA sequencing of G47Δ infected MPNST cells revealed heightened integrated stress response activity and blunted induction of translation-associated programs in the PRC2-deficient state (both p <0.001), consistent with compensatory resistance at the level of viral protein translation. Accordingly, tumor-regulated ICP34.5 HSV limited daily tumor-volume growth to 0.6% (95% CI, −2.9–4.2%), improving upon both G47Δ 2 (8.3%; 4.5–12.2%) and controls (22.5%; 17.4–27.8%). A murine gastrointestinal toxicity phenotype reduced all-cause event-free survival, indicating vector and dosing optimizations are needed to widen the therapeutic window.
Conclusions
H3K27me3 loss creates a paradoxical antiviral state that tumor-selective ICP34.5 overcomes to rescue HSV anti-tumor activity, supporting biomarker-driven viral engineering to exploit the permissive transcriptional state of H3K27me3-deficient MPNSTs.
Key Points
Loss of a key epigenetic mark (H3K27me3) MPNST is a biomarker of susceptibility to oncolytic HSV
H3K27me3-deficient MPNST mounts a compensatory stress response that limits HSV propagation.
Engineered viral gene therapy to overcome the stress response rescues antitumor activity.
Importance of the Study
High-grade MPNST lacks effective systemic therapies, and biomarkers that can guide oncolytic virotherapy are poorly defined. This study identifies loss of PRC2-dependent H3K27me3 as a marker of susceptibility to oncolytic HSV but shows that this same epigenetic state also primes a compensatory integrated stress response that limits productive viral propagation at the level of protein translation. These findings connect a tumor-specific chromatin defect to both enhanced viral permissiveness and a compensatory resistance mechanism. By restoring tumor-selective expression of ICP34.5 , an HSV-encoded antagonist of the integrated stress response frequently removed to promote oncolytic vector attenuation, we demonstrate that this second barrier can be therapeutically targeted to improve antitumor activity. The work therefore provides a mechanistic framework for matching viral engineering to tumor epigenetic state. Robust anti-tumor activity must be balanced with therapeutic safety, providing avenues for further vector optimization. This biomarker-driven strategy may be relevant to other H3K27me3-deficient nervous system tumors.
