Gene expression profiling of hematologic malignant cell lines resistant to oncolytic virus treatment

Abstract

Pexa-Vec (pexastimogene devacirpvec; JX-594) has emerged as an attractive tool in oncolytic virotherapy. Pexa-Vec demonstrates oncolytic and immunotherapeutic mechanisms of action. But the determinants of resistance to Pexa-Vec are mostly unknown. We treated hemoatologic malignant cells with Pexa-Vec and examined the gene-expression pattern of sensitive and resistant cells. Human myeloid malignant cell lines (RPMI-8226, IM-9, K562, THP-1) and lymphoid cancer cell lines (MOLT4, CCRF-CEM, Ramos, U937) were treated with Pexa-Vec. Pexa-Vec was cytotoxic on myeloid cell lines in a dose-dependent manner, and fluorescent imaging and qPCR revealed that Pexa-Vec expression was low in RAMOS than IM-9 after 24 hrs and 48 hrs of infection. Gene expression profiles between two groups were analyzed by microarray. Genes with at least 2-fold increase or decrease in their expression were identified. A total of 660 genes were up-regulated and 776 genes were down-regulated in lymphoid cancer cell lines. The up- and down-regulated genes were categorized into 319 functional gene clusters. We identified the top 10 up-regulated genes in lymphoid cells. Among them three human genes (LEF1, STAMBPL1, and SLFN11) strongly correlated with viral replication. Up-regulation of PVRIG, LPP, CECR1, Arhgef6, IRX3, IGFBP2, CD1d were related to resistant to Pexa-Vec. In conclusion, lymphoid malignant cells are resistant to Pexa-Vec and displayed up-regulated genes associated with resistance to oncolytic viral therapy. These data provide potential targets to overcome resistance, and suggest that molecular assays may be useful in selecting patients for further clinical trials with Pexa-Vec.

Overexpression of Smac by an Armed Vesicular Stomatitis Virus Overcomes Tumor Resistance

“…Immunotherapies with OVs and immune checkpoint inhibitors showed renewed promises for cancer treatment. However, many tumors are resistant to OVs27, 28, 29, 30 or fail to respond to checkpoint inhibitors 31, 32. When cells are infected by OVs, the virus replication causes tremendous stress on the host cells 33 .…”

STAMBPL1 knockdown has antitumour effects on gastric cancer biological activities

“…STAMBPL1 is the main factor of the JAMM family members. Additionally, previous studies have reported high expression levels of STAMBPL1 in cancer tissues and that knockdown of STAMBPL1 could suppress the biological activities of leukaemia via regulation of NF-κB activity (12–14). In the present study, it was also demonstrated that STAMBPL1 protein expression was higher in gastric cancer tissues compared with that in adjacent normal tissues and that the expression levels increased with advanced stages in the clinical samples.…”

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

“…Increased expression of ILT2 on T cells was associated with poor response to oncolytic virotherapy using vaccinia virus [ 157 ]. Another study attempted to identify biomarkers associated with resistance to vaccinia virus therapy in hematological malignancies [ 158 ]. Genes involved in the ubiquitination pathway, DNA damage response and antigen presentation, among others, were identified and associated with resistance to vaccinia virus-induced oncolysis [ 158 ].…”