The TLR-7 Agonist, Imiquimod, Enhances Dendritic Cell Survival and Promotes Tumor Antigen-Specific T Cell Priming: Relation to Central Nervous System Antitumor Immunity

Abstract

Immunotherapy represents an appealing option to specifically target CNS tumors using the immune system. In this report, we tested whether adjunctive treatment with the TLR-7 agonist imiquimod could augment antitumor immune responsiveness in CNS tumor-bearing mice treated with human gp100 + tyrosine-related protein-2 melanoma-associated Ag peptide-pulsed dendritic cell (DC) vaccination. Treatment of mice with 5% imiquimod resulted in synergistic reduction in CNS tumor growth compared with melanoma-associated Ag-pulsed DC vaccination alone. Continuous imiquimod administration in CNS tumor-bearing mice, however, was associated with the appearance of robust innate immune cell infiltration and hemorrhage into the brain and the tumor. To understand the immunological mechanisms by which imiquimod augmented antitumor immunity, we tested whether imiquimod treatment enhanced DC function or the priming of tumor-specific CD8+ T cells in vivo. With bioluminescent, in vivo imaging, we determined that imiquimod dramatically enhanced both the persistence and trafficking of DCs into the draining lymph nodes after vaccination. We additionally demonstrated that imiquimod administration significantly increased the accumulation of tumor-specific CD8+ T cells in the spleen and draining lymph nodes after DC vaccination. The results suggest that imiquimod positively influences DC trafficking and the priming of tumor-specific CD8+ T cells. However, inflammatory responses induced in the brain by TLR signaling must also take into account the local microenvironment in the context of antitumor immunity to induce clinical benefit. Nevertheless, immunotherapeutic targeting of malignant CNS tumors may be enhanced by the administration of the innate immune response modifier imiquimod.

A nonreplicating subunit vaccine protects mice against lethal Ebola virus challenge

“…TLR agonists act as immunomodulators and have been studied as potential adjuvant agents for a variety of vaccines: influenza virus (21), HSV (22), hepatitis B virus (23), and different types of cancer (24,25). After an initial screen of different TLR agonists, based on strongest immunomodulation, we selected PIC, a TLR3 agonist, and CL097, a TLR7/8 agonist, to test in combination with an EIC vaccine.…”

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.…”

Development of Vaccine Adjuvants: A Historical Perspective

“…The use of RNA adjuvant molecules has been diffi cult despite the advent of stabilized RNA derivatives [157]. However, the activity of the imidazoquinoline derivatives, which also stimulate RNA receptors TLR7 and TLR8 [158], have shown preclinical potential as Th1-directing adjuvants for herpes simplex vaccines [159][160][161]. One such product, Imiquimod, has been licensed for topical treatment of herpes simplex [162], but use of imidazoquinoline derivatives as adjuvants remains at preclinical stages.…”