p53 Unleashes Endogenous Retroviruses to Tackle Tumors: Study

“The mechanism is novel,” says Maureen Murphy, a cancer biologist at the Wistar Institute in Philadelphia who studies p53 but was not involved in this study. She also says the study is strong overall and will likely translate clinically.

Harnessing endogenous retroviruses against cancer

Selinova and her colleagues worked with three in vitro human cancer cell lines: melanoma, osteosarcoma, and breast cancer cells. They boosted the activity of p53 in these cells by inhibiting other proteins known to gum up p53’s work: MDM2 and MDMX. (One of the inhibitors they used is a product of Aileron Therapeutics; three authors of the paper work at Aileron).

After the cells were exposed to these inhibitors, quantitative PCR tests revealed that expression of RNA from multiple endogenous human retroviruses increased. These viruses are once-infectious agents that, over evolutionary history, have settled into the genome. They collectively make up an estimated 8 percent of the human genome, and most are inert. Others, however, remain active and do have the potential to cause damage. When active, these viral sequences can multiply and insert themselves into new spots in the genome in harmful ways. That’s why there are several mechanisms in place to protect cells against retroviruses, Selivanova notes—including, usually, activating p53, which in most circumstances blocks the ability of retroviruses to access new parts of the genome.

In the team’s experiments, however, p53 did the exact opposite: it activated retroviruses. The researchers confirmed this using cell lines edited to lack the protein, which didn’t express the viral RNA seen in the other cells. Sequencing of cellular RNA revealed that p53 activated the retroviruses by inhibiting two proteins that normally quash their expression, LSD1 and DNMT1.

With these inhibitors out of the way, the retroviruses set about making copies of themselves in the form of double-stranded RNA—molecules that also happen to be a telltale sign of a viral infection. Although no external pathogens were involved, when they detected the double-stranded RNA, the cells acted as if they were infected, activating antiviral immune pathways, including the production of interferons—proteins that, among other activities, can stimulate ill cells to advertise their condition by sticking bits of their proteins on their outer cell membrane. Immune cells use these cell-surface antigens to identify and target infected cells, so increasing interferon production could translate to the cancerous cells losing their ability to evade immune detection.

See “Viral Remnants Help Regulate Human Immunity”

This apparent infection mimicry also happened in biopsy samples of two people with melanoma. The biopsies were injected with a dual MDM2/MDMX inhibitor (another Aileron product) that boosted the activity of p53, and in both, this increased activity led to greater retroviral expression, interferon activation, and the infiltration of tumor-killing CD8+ T cells.

“It’s an interesting mechanism by which you stimulate the immune system when you activate p53,” says Wafik El-Deiry, an oncology researcher at Brown University. El-Deiry, the first author of a 1992 Nature Genetics paper that shows how p53 binds to genes to suppress tumors, is also working with Aileron Therapeutics to study the benefits of MDM2/MDMX inhibitors.

Connecting cancer treatments

In addition to revealing the unexpected actions of a well-studied tumor suppressor, Murphy says Selivanova and colleagues may have uncovered the missing link as to why using radiation can be an effective way to control cancer. “Something that’s been known forever is that radiation actually enhances these endogenous retroviruses, and nobody put two and two together and said: ‘gee, radiation induces p53, and maybe that’s it.’”

For Selivanova, the next big question is how this mechanism is altered by mutated versions of p53, which she says are present in half of human tumors.

Selivanova says she hopes this knowledge can ultimately help patients. In the study, the researchers were able to shrink melanomas in mice by 75 percent in two weeks by combining an MDM2/MDMX inhibitor with an immune checkpoint inhibitor—an established cancer therapy that invigorates the body’s natural anticancer defenses. In mice with colon cancer, the pharmaceutical combo increased CD8+ T cell production in a manner similar to the retrovirus-interferon pathway in vitro. While this is not the first time researchers have combined boosted p53 with an immune checkpoint inhibitor, the team may have uncovered the hidden retroviral mechanism behind why the combination appears effective in cell lines and mice, says Murphy. Further work on retroviruses’ role could point toward ways to improve upon these therapies and other cancer treatments.