Despite comprising a large fraction of the human genome, the biology and function of endogenous retroelements remains poorly understood.  Endogenous retroelements are largely silenced through epigenetic mechanisms, however these retroelements can be re-expressed in malignancy or via epigenetic therapies.  Recent studies indicate that re-activation of retroelements can promote anti-cancer immune responses through inflammation and viral mimicry.  This session will cover new topics in re-activation of endogenous retroelements and viral mimicry, through hypomethylating agents (HMAs) and other mechanisms, as an emerging area of intense focus for cancer therapy.

Dr. Gabriel Griffin will discuss the topic of reactivation of epigenetically controlled immunogenicity for tumor therapy, including his perspective on the current state of this field and future key directions. He will focus on the function of endogenous retroviruses (ERV) and other transposable elements (TE) as latent immunostimulatory ligands in cancer cells. Dr. Griffin will review epigenetic mechanisms of ERV and TE silencing, as well as the cellular and immunologic sequelae of their activation in cancer cells. Finally, Dr. Griffin will discuss the potential for epigenetic therapies to enhance the efficacy and scope of cancer immunotherapy, including for hematologic cancers.

Dr. Lipka will review the potential mechanisms mediating response to HMAs and discuss the impact of endogeneous retroelement reactivation and viral mimicry upon sensitivity of myeloid neoplasms to HMAs. Understanding these mechanisms is important since HMAs are currently widely used in the treatment of hematologic malignancies, but their exact mechanism of action remains elusive.

Dr. Chiappinelli will present recent work on transcriptional regulation of transposable elements by epigenetic mechanisms and the tumor suppressor P53 and how transposable element RNA can activate the type I interferon response. Transposable elements make up half of the genome and are silenced by epigenetic modifications in most differentiated normal cells. In cancer cells, silencing of transposable elements is altered, and this can further be perturbed by therapies that target epigenetic regulators.