A new discovery from researchers at The University of Texas at Austin and The University of Texas MD Anderson Cancer Center helps explain why some chemotherapy drugs not only eliminate cancer cells directly, they - at least in some patients - actually trigger the innate immune system to attack cancer cells.
The researchers made this discovery while testing a potential chemotherapy agent referred to as Compound 1 - which causes a build-up of toxic molecules called reactive oxygen species - on preclinical models. 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 cells that aren't infected, this effect is called viral mimicry.
When the scientists injected pretreated cancer cells into preclinical models, the immune system responded as if the cells were infected by a virus and needed to be eliminated. Moreover, the immune system remained primed to attack future cancer cells, including those that were left untreated. This viral mimicry has been seen with other cancer-treating agents, suggesting the immune system's ability to detect these anti-viral signals may be a key driver of the antitumor response seen with other chemotherapies.
"Initially, it didn't make sense as to 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."
Additional studies will be needed to confirm whether viral mimicry is the responsible mechanism that triggers an immune response with other agents. This latest study suggests that it may be possible to recruit the immune system as a critical ally alongside chemotherapy, perhaps offering opportunities to lower the doses for chemotherapy drugs.
"What's most exciting to me is the clinical ramification that maybe you could be using less chemotherapy 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 and exploring combinations with immunotherapy, a type of cancer treatment that also stimulates the immune system to eliminate cancer cells through different mechanisms.
"That might help identify combinations and dosing schedules that better engage the immune system, such as 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.
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/UT MD Anderson Collaborative Pilot Project Grant.
Cancer patients may be treated with a variety of chemotherapies because cancer cells can develop resistance over time. But a lower dose of chemo might also thwart this tendency, Levine explained.
"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 chemotherapy than others. The answer might depend 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.
The chemotherapy discovery stems from longstanding research collaborations between UT and UT MD Anderson. The University of Texas Medical Center, opening in Austin in 2030, will include integrated, world-class cancer care through its partnership with UT MD Anderson.
