Abstract
As a topical cancer immunotherapy, the toll-like receptor 7 ligand imiquimod activates tumor regression via stimulation of immune cell infiltration and cytotoxic responses. Imiquimod also exerts direct pro-apoptotic effects on tumor cells in vitro, but a role for these effects in imiquimod-induced tumor regression remains undefined. We previously demonstrated that cell lines derived from devil facial tumor disease (DFTD), a transmissible cancer threatening the survival of the Tasmanian devil (Sarcophilus harrisii), are sensitive to imiquimod-induced apoptosis. In this study, the pro-apoptotic effects of imiquimod in DFTD have been investigated using RNA-sequencing and label-free quantitative proteomics. This analysis revealed that changes to gene and protein expression in imiquimod treated DFTD cells are consistent with the onset of oxidative and endoplasmic reticulum stress responses, and subsequent activation of the unfolded protein response, autophagy, cell cycle arrest and apoptosis. Imiquimod also regulates the expression of oncogenic pathways, providing a direct mechanism by which this drug may increase tumor susceptibility to immune cytotoxicity in vivo. Our study has provided the first global analysis of imiquimod-induced effects in any tumor cell line. These findings have highlighted the potential of cell stress pathways as therapeutic targets in DFTD, and will allow for improved mechanistic use of imiquimod as a therapy in both the Tasmanian devil and human cancers.
Highlights
Imiquimod (R-837), an imidazoquinoline analogue of guanosine, is a potent immune modifier [1]
We previously demonstrated that cell lines derived from devil facial tumor disease (DFTD), a transmissible cancer threatening the survival of the Tasmanian devil (Sarcophilus harrisii), are sensitive to imiquimod-induced apoptosis
After application of quality control filters described in the methods, 13,559 gene transcripts were detected by RNA sequencing (RNA-seq) and 1057 proteins were detected by nanoHPLCMS in DFT1 cells (Figure 1A and 1B)
Summary
Imiquimod (R-837), an imidazoquinoline analogue of guanosine, is a potent immune modifier [1]. Known as an agonist of the viral single stranded RNA sensor toll-like receptor 7 (TLR7), imiquimod has attracted interest in clinical immunotherapy trials for its anti-viral and anti-tumor properties [1,2,3]. It is approved by the FDA as a topical immunotherapy against external genital and perianal warts, actinic keratosis and superficial basal cell carcinoma [2]. This ability of imiquimod to act on the immune response at multiple levels could account for its success as an anti-cancer drug
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