Immunoglobulin-like transcript 2 (ILT2) is a biomarker of therapeutic response to oncolytic immunotherapy with vaccinia viruses.
BACKGROUND
Oncolytic viruses represent a novel form of cancer immunotherapy. Vaccinia viruses encoding human T cell co-stimulatory molecules have demonstrated clinical activity in phase I clinical trials in patients with advanced melanoma. However, predictive biomarkers of therapeutic response have not yet been identified.


METHODS
A customized microarray was performed to identify changes in peripheral blood mononuclear cell (PBMC) gene expression upon exposure to recombinant oncolytic vaccinia viruses. Up-regulated and down-regulated genes were identified and selected for further analysis using PBMC samples from normal donors and oncolytic virus-treated patients before and after viral injection. Quantitative PCR and flow cytometry of defined T cell subsets was performed to evaluate expression patterns and clinical correlations.


RESULTS
The microarray identified 301 genes that were up-regulated and 960 genes that were down-regulated in T cells after exposure to oncolytic vaccinia virus. The B7.1 gene was highly up-regulated and the immunoglobulin-like transcript 2 (ILT2) gene was highly down-regulated by vaccinia-B7.1, which was consistent with the known inverse regulation of these two genes. We observed an inverse association between ILT2 expression in the tumor microenvironment and clinical response and further identified ILT2 as a marker of regulatory CD4+ and suppressor CD8+ T cell responses and whose down-regulation was predictive of therapeutic responses in patients treated with oncolytic virus immunotherapy.


CONCLUSIONS
ILT2 is a new putative biomarker of T cell and clinical response in patients treated with oncolytic vaccinia virus immunotherapy. Further confirmation of ILT2 as a biomarker requires prospective validation in a larger series of clinical trials.
Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA ; Department of Immunology/Microbiology, Rush University Medical Center, 1750 West Harrison Street, Chicago, IL 60612, USA.
Andrew
A
Zloza
Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA.
Dae Won
DW
Kim
The Tumor Immunology Laboratory, Department of Surgery, Mount Sinai School of Medicine, One Gustave L. Levy Place, New York, NY 10029, USA.
Seunghee
S
Kim-Schulze
Rush University Cancer Center, 1725 West Harrison Street, Chicago, IL 60612, USA.
Michael C
MC
Jagoda
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA ; Department of Pathology and Diagnostic, University of Verona Medical School, Verona, Italy.
Vladia
V
Monsurro
Infectious Disease and Immunogenetics Section, Department of Transfusion Medicine, Clinical Center, National Institutes of Health, 9000 Rockville Pike, Bethesda, MD 20892, USA ; Research Branch, Sidra Medical and Research Centre, Doha, Qatar.
Francesco M
FM
Marincola
Rutgers Cancer Institute of New Jersey, 195 Little Albany Street, New Brunswick, NJ 08903, USA.
Howard L
HL
Kaufman
Biomarker; Cancer vaccines; Immunoglobulin-like transcript 2; Immunotherapy; Oncolytic virus; T cells; Vaccinia