Tumor-Preferential Induction of Immune Responses and Epidermal Cell Death in Actinic Keratoses by Ingenol Mebutate

The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolv...

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Bibliographic Details
Published in:PloS one 2016-09, Vol.11 (9), p.e0160096-e0160096
Main Authors: Emmert, Steffen, Haenssle, Holger A, Zibert, John R, Schön, Margarete, Hald, Andreas, Hansen, Maria H, Litman, Thomas, Schön, Michael P
Format: Article
Language:English
Subjects:
Administration, Topical
Adult
Analysis
Apoptosis
Biochemistry
Biology and life sciences
Biomarkers
Cancer
CD4 antigen
CD8 antigen
Cell activation
Cell death
Cell Death - drug effects
Chemokines
Cluster Analysis
Dermatology
Diterpenes - pharmacology
Diterpenes - therapeutic use
Epidermis - drug effects
Epidermis - immunology
Epidermis - metabolism
Epidermis - pathology
Gene clusters
Gene Expression
Gene Expression Profiling
Humans
Immune response
Immunity
Immunity, Innate
Inflammation
Innate immunity
Intercellular adhesion molecule 1
Keratosis
Keratosis, Actinic - drug therapy
Keratosis, Actinic - etiology
Keratosis, Actinic - metabolism
Keratosis, Actinic - pathology
Kinases
Leukocytes (neutrophilic)
Leukocytes - immunology
Leukocytes - metabolism
Leukocytes - pathology
Lymphocytes T
Macrophages
Medicine and Health Sciences
MicroRNA
MicroRNAs
MicroRNAs - genetics
miRNA
Mode of action
Patients
RNA, Messenger - genetics
Skin
Stem cells
T cells
Tumors
Wounding
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Summary:The rapid and strong clinical efficacy of the first-in-class, ingenol mebutate, against actinic keratosis (AK) has resulted in its recent approval. We conducted the first comprehensive analysis of the cellular and molecular mode of action of topical ingenol mebutate 0.05% gel in both AK and uninvolved skin of 26 patients in a phase I, single-center, open-label, within-patient comparison. As early as 1 day after application, ingenol mebutate induced profound epidermal cell death, along with a strong infiltrate of CD4+ and CD8+ T-cells, neutrophils, and macrophages. Endothelial ICAM-1 activation became evident after 2 days. The reaction pattern was significantly more pronounced in AK compared with uninvolved skin, suggesting a tumor-preferential mode of action. Extensive molecular analyses and transcriptomic profiling of mRNAs and microRNAs demonstrated alterations in gene clusters functionally associated with epidermal development, inflammation, innate immunity, and response to wounding. Ingenol mebutate reveals a unique mode of action linking directly to anti-tumoral effects. ClinicalTrials.gov NCT01387711.
ISSN:1932-6203
1932-6203
DOI:10.1371/journal.pone.0160096