Tumoricidal activity of TLR7/8-activated inflammatory dendritic cells

Abstract

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.

Trafficking properties of plasmacytoid dendritic cells in health and disease

“…In a clinical study, TLR-dependent activation of PDCs contributed to rejection of cutaneous tumors. In this condition, PDCs produced type I IFN, expressed TRAIL and localized together with T cells and NK cells [25]. Interestingly, a new cell population of CD11c + myeloid DCs endowed with tumoricidal potential was identified in these lesions [25].…”

“…In this condition, PDCs produced type I IFN, expressed TRAIL and localized together with T cells and NK cells [25]. Interestingly, a new cell population of CD11c + myeloid DCs endowed with tumoricidal potential was identified in these lesions [25]. The relevance of PDCs in cancer immunosurveillance has been recently shown in mice [68,69], where TLR9-activated PDCs lead to the regression of subcutaneous B16 melanoma tumors, by orchestrating the sequential activation of NK cells, MDCs and CD8 + T cells.…”

“…Finally, inflammatory chemokines can attract activated T cells to sites of inflammation [20]. Interestingly, it has been shown that PDCs can induce apoptosis of tumour and virus-infected cell lines, either directly by secreting TRAIL (TNF-related apoptosis-inducing ligand) upon activation, or indirectly via the effect of type I IFN on other cytotoxic cells [24,25]. PDCs contain abundant granzyme B, but the role of this enzyme as a cytotoxic molecule remains elusive, because PDCs, in contrast to other cytotoxic cells, lack the pore-forming perforin [1,26].…”

The ‘kiss of death’ by dendritic cells to cancer cells

“…76 Surprisingly, TLR-7/8-activated human blood-derived DCs demonstrated a Ca 2 þ -dependent cytotoxicity toward tumor cells, evoking a granule exocytosis-dependent mechanism. 54 The authors observed that the basal skin carcinoma-infiltrating CD11c þ DCs co-stained for PRF and GZM and DCs isolated from peripheral blood of those cancer patients exhibit cytotoxicity. However, there was no direct evidence that the cytotoxic DCs isolated from peripheral blood were indeed the same as the PRF/GRZ þ CD11c þ DC infiltrating the tumors.…”

The TLR7 agonists imiquimod and gardiquimod improve DC-based immunotherapy for melanoma in mice

“…13 After being recognized by TLR7 or TLR8, these ligands activate intracellular signaling pathways leading to the induction of type I IFNs, proinflammatory cytokines and chemokines. 5,13 The major benefit of TLR7/8 agonists is that they not only activate antigen-presenting cells, [14][15][16] but also promote activation of T and NK cells and inhibit regulatory T cell function. 13,[17][18][19][20] Moreover, TLR7/8 ligands have been shown to directly affect some tumor cells by inducing apoptosis and sensitizing tumor cells to killing mediated by CTLs and chemotherapeutic agents.…”