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

Commun Biol. 2021 Mar 3;4(1):276. doi: 10.1038/s42003-021-01800-3.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adjuvants, Immunologic / pharmacology*
  • Animals
  • Antineoplastic Combined Chemotherapy Protocols / pharmacology*
  • Apoptosis / drug effects
  • Cell Line, Tumor
  • Depsipeptides / pharmacology
  • Endogenous Retroviruses / drug effects*
  • Endogenous Retroviruses / genetics
  • Endogenous Retroviruses / metabolism
  • Female
  • Histone Deacetylase Inhibitors / pharmacology*
  • Humans
  • Imiquimod / pharmacology
  • Immunity, Innate / drug effects
  • Mice
  • Mice, Nude
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / virology
  • Pteridines / pharmacology
  • Signal Transduction
  • Toll-Like Receptor 7 / agonists*
  • Toll-Like Receptor 7 / genetics
  • Toll-Like Receptor 7 / metabolism
  • Tumor Cells, Cultured
  • Viral Envelope Proteins / genetics
  • Viral Envelope Proteins / metabolism
  • Virus Activation / drug effects*
  • Vorinostat / pharmacology
  • Xenograft Model Antitumor Assays

Substances

  • Adjuvants, Immunologic
  • Depsipeptides
  • Histone Deacetylase Inhibitors
  • Pteridines
  • Toll-Like Receptor 7
  • Viral Envelope Proteins
  • Vorinostat
  • romidepsin
  • vesatolimod
  • Imiquimod