In recent years, scientists have discovered that some chemotherapy drugs not only kill cancer cells directly, but at least in some patients, mysteriously also trigger their immune system to attack the cancer. That would seem all but impossible, given that the immune system has a built-in safety mechanism called "self-tolerance" that blocks it from attacking a person's own cells, even abnormal cells, meaning ones that have become cancerous.
A new discovery from researchers at The University of Texas at Austin and UT MD Anderson Cancer Center suggests a solution to this mystery, and it has the potential to revolutionize how doctors treat cancer.
The researchers were testing a potential chemotherapy agent referred to as Compound 1—that causes a build-up of toxic molecules called reactive oxygen species—on mouse cancer cells when they made the startling discovery. The experimental drug caused cancer cells to release the same kinds of signals that normal cells release when they've been infected by a virus. In fact, the tip-off was a signal similar to one observed in people infected with the virus that causes COVID. In cells that aren't actually infected, this effect is called viral mimicry.
When the scientists injected these treated cancer cells into mice, their immune systems responded as if to a recently infected cell that was signaling it needed to be eliminated to prevent viral particles from escaping and infecting more cells. Their immune systems remained primed to attack, even when untreated cancer cells were later injected.
"It didn't make sense why chemotherapies sometimes generated an immune response," said Brent Iverson, the Warren J. and Viola Mae Raymer Professor of chemistry at UT and co-author of a recent paper describing the work in the Proceedings of the National Academy of Sciences . "Why did the immune system see these cancer cells as not being 'self' and attack them? But now we can connect the dots. The cancer cells are acting like they're infected."
For existing chemotherapy drugs known to induce the kind of cancer cell death that triggers an immune response, the researchers say, additional study will be needed to confirm whether viral mimicry is the mechanism responsible. But if it is, the implications could be profound for future cancer treatment approaches.
With conventional chemotherapy, the goal is to exterminate every cancer cell, even if that means also wiping out some, or all, of a patient's immune system. It's a kind of scorched-earth approach. This latest study suggests that the immune system can instead be recruited as a critical ally in the battle. Perhaps, the team suggested, a more effective strategy would be using lower doses of chemotherapy drugs.
"What's most exciting to me is the clinical ramification that maybe you should be using less rat poison on patients to have a better outcome, so less might be more," said Jonathan Sessler, a cancer survivor himself and the R. P. Doherty, Jr. - Welch Regents Chair in Chemistry at UT. Sessler developed Compound 1 and was a co-author on the paper.
The team's future work will include screening existing chemotherapy drugs for their ability to induce viral mimicry.
"That might help identify combinations and dosing schedules that better engage the immune system, for example by pairing cytotoxic drugs with immunotherapies in a way that maximizes immune activation while avoiding excessive damage to immune cells themselves," said Matthew Levine, a UT chemistry graduate student who led the research. Immunotherapy is a different cancer-treatment approach that also commissions the body's immune system for action in fighting cancerous cells, using a different mechanism.
Lauren Ehrlich, a UT professor of molecular biosciences specializing in immunology, and Ronald DePinho, a professor of cancer biology at the UT MD Anderson Cancer Center, were additional primary contributors on the research.
This work was supported in part by the National Institutes of Health (NIH) and the Robert A. Welch Foundation. Additional support was provided by a UT Austin/MD Anderson Cancer Center Collaborative Pilot Project Grant.
Cancer patients are often treated with a variety of different chemotherapeutics over time because cancer cells tend to eventually develop resistance. But a lower dose of chemo might also thwart this tendency, Levine observed.
"If our viral mimicry hypothesis is correct, one of the potential breakthroughs of this approach over traditional treatment is that since this plan harnesses lower dose and primarily relies more on the host immune system, one might not have to treat tumors multiple times," Levine said. "This would ultimately mean that these tumors might have less of a chance to develop resistance to treatment."
The study might also help explain why some people respond much better to the same chemotherapeutic than others. The answer might depend on how much of a person's immune system is left intact after treatment, on specific differences between different people's immune systems or on how well a drug induces viral mimicry.
"We are currently seeking clinical collaborations so that we can analyze samples from patients that have been treated with chemotherapeutic agents to see if there is a correlation between the differences in survival and the markers that are associated with viral mimicry," Levine said.
