Sanlorenzo and Novoszel et al. showed that combining oral and topical imiquimod (IMQ) treatment inhibited growth of directly treated tumors and distal metastases. Oral IMQ systemically stimulated TLR7/8+ pDCs to produce IFN-I. IFN-I upregulated TLR7/8 on intratumoral myeloid cells to enable topical IMQ to stimulate IFN-I/Jun/AP-1-signaled TLR7+DCs to produce IL-12 and pDC-recruiting CCL2. IL-12 acted directly on tumor cells to reduce VEGFA levels, resulting in tumor necrosis. Combination IMQ therapy (or IFNα and topical IMQ) induced CD8+ TEFF/MEM cells, ICB sensitivity, and immunologic memory. IFNα upregulated DC-specific TLR7/8 in patients with melanoma.
Contributed by Paula Hochman
ABSTRACT: Dendritic cell (DC) activation by pattern recognition receptors like Toll-like-receptors (TLRs) is crucial for cancer immunotherapies. Here, we demonstrate the effectiveness of the TLR7/8 agonist imiquimod (IMQ) in treating both local tumors and distant metastases. Administered orally, IMQ activates plasmacytoid DCs (pDCs) to produce systemic type I interferons (IFN-I) required for TLR7/8 upregulation in DCs and macrophages, sensitizing them to topical IMQ treatment, which is essential for therapeutic efficacy. The mechanism involves c-Jun/AP-1 mediating TLR7/8 signaling in IFN-I-primed DCs, upregulating the pDC-recruiting chemokine CCL2 and the anti-angiogenic cytokine interleukin-12, which suppresses VEGF-A production leading to tumor necrosis and regression. Combining topical and systemic IMQ or IFN-I generates a CD8(+) T cell-dependent response at metastatic sites, reinforced by PD-1 blockade, leading to long-lasting memory. Analysis of cohorts of patients with melanoma demonstrates DC-specific TLR7/8 upregulation by IFN-I, supporting the translational potential of combining systemic IFN-I and topical IMQ to improve immunotherapy of topically accessible tumors.
Author Info: (1) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (2) Center for Cancer Research, Medical University of Vienna, Comprehens
Author Info: (1) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (2) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (3) Department of Dermatology, Klinik Landstrasse, Vienna, Austria. (4) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (5) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (6) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (7) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (8) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (9) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (10) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (11) Department of Dermatology, Klinik Landstrasse, Vienna, Austria. (12) Department of Dermatology, Klinik Landstrasse, Vienna, Austria. (13) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. (14) Center for Cancer Research, Medical University of Vienna, Comprehensive Cancer Center, Vienna, Austria. maria.sibilia@meduniwien.ac.at.
