Human endogenous retroviruses and their implication for immunotherapeutics of cancer

Human endogenous retroviruses (HERVs) have recently caught increased attention as a potential internal trigger to sensitize tumor cells to immunotherapies. HERVs are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny. Today, HERVs constitute ∼8% of the human genome, but most elements are highly degenerated, under strict epigenetic regulation, and rarely expressed in healthy tissues. However, cancer cells are specifically prone to reactivate the expression of HERV elements due to epigenetic dysregulation that accumulate during malignant transformation and when using epigenetic therapies. HERV expression can induce an interferon response due to induction of the viral defense pathway, so-called 'viral mimicry'. By mimicking viral infections, HERVs could function as an 'intrinsic adjuvant', possibly sensitizing cancer cells to immunological recognition. Furthermore, translated HERV elements may in themselves form a valuable pool of tumor-associated antigens. Epitopes derived from HERVs have been recognized by cytotoxic CD8+ T cells, leading to cancer cell recognition. The combination of 'viral mimicry' and T-cell recognition could provide a powerful combination with existing immune stimulatory therapies, such as checkpoint inhibition. This combination is currently being evaluated in clinical trials in a large number of cancers.