Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors
David Díaz-Carballo, Sahitya Saka, Ali H. Acikelli, Ekaterina Homp, Julia Erwes, Rebecca Demmig, Jacqueline Klein, Katrin Schröer, Sascha Malak, Flevy D’Souza, Adrien Noa-Bolaño, Saskia Menze, Emilio Pano, Swetlana Andrioff, Marc Teipel, Philip Dammann, Diana Klein, Amber Nasreen, Andrea Tannapfel, Nicole Grandi, Enzo Tramontano, Crista Ochsenfarth, Dirk Strumberg
Abstract
In this work, we are reporting that "Shock and Kill", a therapeutic approach designed to eliminate latent HIV from cell reservoirs, is extrapolatable to cancer therapy. This is based on the observation that malignant cells express a spectrum of human endogenous retroviral elements (HERVs) which can be transcriptionally boosted by HDAC inhibitors. The endoretroviral gene HERV-V2 codes for an envelope protein, which resembles syncytins. It is significantly overexpressed upon exposure to HDAC inhibitors and can be effectively targeted by simultaneous application of TLR7/8 agonists, triggering intrinsic apoptosis. We demonstrated that this synergistic cytotoxic effect was accompanied by the functional disruption of the TLR7/8-NFκB, Akt/PKB, and Ras-MEK-ERK signalling pathways. CRISPR/Cas9 ablation of TLR7 and HERV-V1/V2 curtailed apoptosis significantly, proving the pivotal role of these elements in driving cell death. The effectiveness of this new approach was confirmed in ovarian tumour xenograft studies, revealing a promising avenue for future cancer therapies.