Oncolytic viruses induce local tumor destruction and inflammation. Whether virotherapy can also overcome immunosuppression in noninfected tumor areas is under debate. To address this question, we have explored immunologic effects of oncolytic herpes simplex viruses (oHSVs) in a genetically engineered mouse model of isocitrate dehydrogenase (IDH) wild-type glioblastoma, the most common and most malignant primary brain tumor in adults. Our model recapitulates the genomics, the diffuse infiltrative growth pattern, and the extensive macrophage-dominant immunosuppression of human glioblastoma. Infection with an oHSV that was armed with a UL16-binding protein 3 (ULBP3) expression cassette inhibited distant tumor growth in the absence of viral spreading (abscopal effect) and yielded accumulation of activated macrophages and T cells. There was also abscopal synergism of oHSVULBP3 with anti–programmed cell death 1 (anti–PD-1) against distant, uninfected tumor areas; albeit consistent with clinical trials in patients with glioblastoma, monotherapy with anti–PD-1 was ineffective in our model. Arming oHSV with ULBP3 led to upregulation of antigen processing and presentation gene sets in myeloid cells. The cognate ULBP3 receptor NKG2D, however, is not present on myeloid cells, suggesting a noncanonical mechanism of action of ULBP3. Overall, the myeloid-dominant, anti–PD-1–sensitive abscopal effect of oHSVULBP3 warrants further investigation in patients with IDH wild-type glioblastoma.
Hans-Georg Wirsching, Huajia Zhang, Frank Szulzewsky, Sonali Arora, Paola Grandi, Patrick J. Cimino, Nduka Amankulor, Jean S. Campbell, Lisa McFerrin, Siobhan S. Pattwell, Chibawanye Ene, Alexandra Hicks, Michael Ball, James Yan, Jenny Zhang, Debrah Kumasaka, Robert H. Pierce, Michael Weller, Mitchell Finer, Christophe Quéva, Joseph C. Glorioso, A. McGarry Houghton, Eric C. Holland
Usage data is cumulative from May 2023 through May 2024.
Usage | JCI | PMC |
---|---|---|
Text version | 1,736 | 97 |
23 | 37 | |
Figure | 47 | 0 |
Supplemental data | 22 | 3 |
Citation downloads | 7 | 0 |
Totals | 1,835 | 137 |
Total Views | 1,972 |
Usage information is collected from two different sources: this site (JCI) and Pubmed Central (PMC). JCI information (compiled daily) shows human readership based on methods we employ to screen out robotic usage. PMC information (aggregated monthly) is also similarly screened of robotic usage.
Various methods are used to distinguish robotic usage. For example, Google automatically scans articles to add to its search index and identifies itself as robotic; other services might not clearly identify themselves as robotic, or they are new or unknown as robotic. Because this activity can be misinterpreted as human readership, data may be re-processed periodically to reflect an improved understanding of robotic activity. Because of these factors, readers should consider usage information illustrative but subject to change.