Modulation of viability and maturation of human monocyte-derived dendritic cells by oncolytic adenoviruses.
Adenoviral oncolysis is a promising new modality for treatment of cancer based on selective viral replication in tumor cells. However, tumor cell killing by adenoviral oncolysis needs to be improved to achieve therapeutic benefit in the clinic. Towards this end, the activation of anti-tumor immunity by adenoviral oncolysis might constitute a potent mechanism for systemic killing of uninfected tumor cells, thereby effectively complementing direct tumor cell killing by the virus. Knowledge of anti-tumor immune induction by adenoviral oncolysis, however, is lacking mostly due to species-specificity of adenovirus replication, which has hampered studies of human oncolytic adenoviruses in animals. We suggest the analysis of interactions of oncolytic adenoviruses with human immune cells as rational basis for the implementation of adenoviral oncolysis-induced anti-tumor immune activation. The goal of our study was to investigate how oncolytic adenoviruses affect human dendritic cells (DCs), key regulators of innate and adoptive immunity that are widely investigated as tumor vaccines. We report that melanoma-directed oncolytic adenoviruses, like replication-deficient adenoviruses but unlike adenoviruses with unrestricted replication potential, are not toxic to monocyte-derived immature DCs and do not block DC maturation by external stimuli. Of note, this is in contrast to reports for other viruses/viral vectors and represents a prerequisite for anti-tumor immune activation by adenoviral oncolysis. Furthermore, we show that these oncolytic adenoviruses alone do not or only partially induce DC maturation. Thus additional signals are required for optimal immune activation. These could be delivered, for example, by inserting immunoregulatory transgenes into the oncolytic adenovirus genome.
Schierer
Stephan
S
Department of Dermatology, University Hospital Erlangen, Erlangen, Germany.
Hesse
Andrea
A
Müller
Ina
I
Kämpgen
Eckhart
E
Curiel
David T
DT
Schuler
Gerold
G
Steinkasserer
Alexander
A
Nettelbeck
Dirk M
DM
D000260:Adenoviruses, Human / Q000502:physiology*; D002470:Cell Survival; D002478:Cells, Cultured; D003588:Cytopathogenic Effect, Viral; D003713:Dendritic Cells / Q000166:cytology / Q000378:metabolism / Q000821:virology*; D005822:Genetic Vectors; D006801:Humans; D018664:Interleukin-12 / Q000378:metabolism; D015603:Keratinocytes / Q000166:cytology / Q000378:metabolism / Q000821:virology; D008156:Luciferases / Q000378:metabolism; D008545:Melanoma / Q000473:pathology* / Q000821:virology; D009000:Monocytes / Q000166:cytology / Q000821:virology*; D050130:Oncolytic Virotherapy; D013601:T-Lymphocytes / Q000378:metabolism / Q000821:virology; D014779:Virus Replication
D018664:Interleukin-12; D008156:Luciferases