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

TY - JOUR

T1 - Tumor-Preferential Induction of Immune Responses and Epidermal Cell Death in Actinic Keratoses by Ingenol Mebutate

AU - Emmert, Steffen

AU - Haenssle, Holger A

AU - Zibert, John R

AU - Schön, Margarete

AU - Hald, Andreas

AU - Hansen, Maria H

AU - Litman, Thomas

AU - Schön, Michael P

PY - 2016/9

Y1 - 2016/9

N2 - 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, withinpatient 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.

AB - 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, withinpatient 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.

KW - Administration, Topical

KW - Adult

KW - Biomarkers

KW - Cell Death/drug effects

KW - Cluster Analysis

KW - Diterpenes/pharmacology

KW - Epidermis/drug effects

KW - Gene Expression

KW - Gene Expression Profiling

KW - Humans

KW - Immunity, Innate

KW - Keratosis, Actinic/drug therapy

KW - Leukocytes/immunology

KW - MicroRNAs/genetics

KW - RNA, Messenger/genetics

U2 - 10.1371/journal.pone.0160096

DO - 10.1371/journal.pone.0160096

M3 - Journal article

C2 - 27612149

SN - 1932-6203

VL - 11

SP - e0160096

JO - PLOS ONE

JF - PLOS ONE

IS - 9

ER -