From the Journals

Endogenous retroviruses may unlock new immunotherapy targets



Future epigenetic drugs could activate human endogenous retroviruses (HERVs) in cancer cells to enable immunotherapy, investigators suggest.

Activated HERVs may sensitize cancer cells or serve as novel tumor-associated antigenic targets, reported Anders Steenholdt Attermann, PhD, of the department of micro- and nanotechnology at the Technical University of Denmark in Kongens Lyngby, and colleagues.

A remarkable 8% of the human genome is composed of HERVs.

“They are remnants of retroviral germline infections that resulted in chromosomal integration into all the cells of the progeny, but their viral replication is defective in the present-day human genome,” the authors wrote in Annals of Oncology.

The therapeutic potential for these remnants is complex, as is their relationship with the immune system and neoplasia. Studies dating back to 2002 have found unique associations between HERVs and various types of cancer, including renal cell carcinoma, melanoma, gastrointestinal cancer, colorectal cancer, and breast cancer.

“Early data point towards distinct features for the expression profiles of different HERVs,” the authors wrote, “but these characteristics remain to be fully elucidated. There may be substantial differences in their biological effects, potential roles in immune sensitization, and ability to form an antigen reservoir.”

HERVs may be activated by cancer or epigenetic drugs. While certain cancers may activate particular HERVs into targetable antigens, other cancer-activated HERVs actually shield tumors from the immune system. Still other HERVs require epigenetic drugs for activation, such as DNA methyltransferase inhibitors. These drugs could transform HERVs into “intrinsic adjuvants” or novel antigens; either of which may improve the efficacy of existing immunotherapies like checkpoint inhibitors.

To leverage HERVs for immunotherapy, a better understanding of immune tolerance is needed. Some research suggests that since HERVs share similarities with exogenous viruses, tolerance to HERVs must be incomplete to allow for immune responses to exogenous viruses. In contrast, incomplete tolerance would conceivably lead to autoimmune disease.

“Hence, peripheral tolerance and ignorance mechanisms may play prominent roles in the control of HERV-specific T-cell recognition in healthy individuals,” the authors wrote. “Understanding the differences in HERV expression in the thymus and peripheral tissues would be of great importance for the use of HERVs as immunotherapeutic targets.”

When more clearly understood, HERVs may feature in emerging combination therapies.

“The combination of epigenetic drugs and immunotherapy is exciting for future cancer therapy,” the authors wrote, “especially for cancer types with low mutational burden that respond poorly to immunotherapy or cancer types with poor responses to immune checkpoint inhibitor treatment.”

It appears that the authors’ excitement is shared – almost 50 clinical trials are currently studying epigenetic drug/immunotherapy combinations.

Study funding was provided by the Lundbeck Foundation Fellowship, the European Research Council, the stand-up-to-cancer (SU2C) epigenetic dream team, and StG 677268 NextDART.

SOURCE: Attermann et al. Ann Oncol. 2018 Sep 18. doi: 10.1093/annonc/mdy413.

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