Enhanced antitumoral activity of TLR7 agonists via activation of human endogenous retroviruses by HDAC inhibitors.

Díaz-Carballo, David; Saka, Sahitya; Acikelli, Ali H; Homp, Ekaterina; Erwes, Julia; Demmig, Rebecca; Klein, Jacqueline; Schröer, Katrin; Malak, Sascha; D'Souza, Flevy; Noa-Bolaño, Adrien; Menze, Saskia; Pano, Emilio; Andrioff, Swetlana; Teipel, Marc; Dammann, Philip; Klein, Diana; Nasreen, Amber; Tannapfel, Andrea; Grandi, Nicole; Tramontano, Enzo; Ochsenfarth, Crista; Strumberg, Dirk

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.