Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells

G Stary, C Bangert, M Tauber, R Strohal… - The Journal of …, 2007 - rupress.org
G Stary, C Bangert, M Tauber, R Strohal, T Kopp, G Stingl
The Journal of experimental medicine, 2007rupress.org
Imiquimod (IMQ), a synthetic agonist to Toll-like receptor (TLR) 7, is being successfully used
for the treatment of certain skin neoplasms, but the exact mechanisms by which this
compound induces tumor regression are not yet understood. While treating basal cell
carcinoma (BCC) patients with topical IMQ, we detected, by immunohistochemistry, sizable
numbers of both myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) within the
inflammatory infiltrate. Surprisingly, peritumoral mDCs stained positive for perforin and …
Imiquimod (IMQ), a synthetic agonist to Toll-like receptor (TLR) 7, is being successfully used for the treatment of certain skin neoplasms, but the exact mechanisms by which this compound induces tumor regression are not yet understood. While treating basal cell carcinoma (BCC) patients with topical IMQ, we detected, by immunohistochemistry, sizable numbers of both myeloid dendritic cells (mDCs) and plasmacytoid DCs (pDCs) within the inflammatory infiltrate. Surprisingly, peritumoral mDCs stained positive for perforin and granzyme B, whereas infiltrating pDCs expressed tumor necrosis factor–related apoptosis-inducing ligand (TRAIL). The biological relevance of this observation can be deduced from our further findings that peripheral blood–derived CD11c+ mDCs acquired antiperforin and anti–granzyme B reactivity upon TLR7/8 stimulation and could use these molecules to effectively lyse major histocompatibility complex (MHC) class Ilo cancer cell lines. The same activation protocol led pDCs to kill MHC class I–bearing Jurkat cells in a TRAIL-dependent fashion. While suggesting that mDCs and pDCs are directly involved in the IMQ-induced destruction of BCC lesions, our data also add a new facet to the functional spectrum of DCs, ascribing to them a major role not only in the initiation but also in the effector phase of the immune response.
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