Aggressive ovarian tumors begin as malignant cells kept in check by the immune system until, suddenly and unpredictably, they explode into metastatic cancer. New findings from scientists at The Wistar Institute demonstrate that ovarian tumors don't necessarily break "free" of the immune system, rather dendritic cells of the immune system seem to actively support the tumor's escape. The researchers show that it might be possible to restore the immune system by targeting a patient's own dendritic cells.
"Our model shows where the cancer is kept in check for relatively long periods, but once they become noticeable, tumors grow exponentially," said José R. Conejo-Garcia, M.D., Ph.D., an associate professor at Wistar and leader of the Tumor Microenvironment and Metastasis Program of Wistar's Cancer Center. "More importantly, we show that by depleting these dendritic cells of the immune system, we can reverse the effect, once again allowing our immune system to recognize the ovarian tumors."
Their findings, presented in the March issue of the Journal of Experimental Medicine, available online now, represent the first successful attempt to model the tumor microenvironment of human ovarian cancer in a mouse model of the disease. In essence, the model replicates the inflammatory surroundings that ovarian tumors experience in humans. The more accurate model provides a better tool for researchers to understand, prevent, and treat tumors.
"Our system uses oncogene-driven tumors that are spontaneously antigenic, thus avoiding the use of artificial foreign antigens that do not accurately replicate what drives anti-tumor immune responses in humans," Conejo-Garcia said.
Ovarian cancer remains one of the most deadly forms of cancer in women. According to the National Cancer Institute, 21,990 women will be diagnosed with ovarian cancer, and 15,460 women will die of the disease this year Because early-stage ovarian cancer does not often exhibit noticeable symptoms, many women are not diagnosed until the cancer is at a later stage, when it is most difficult to treat.
"While we have seen an increase in survival rates for most cancers over the last 40 years, ovarian cancer survival has only improved slightly since the 1970's," Conejo-Garcia said. "We created our ovarian cancer model to get a better understanding of how these tumors acquire such aggressive characteristics and evade the immune system."
According to Conejo-Garcia, their model demonstrates how a localized ovarian tumor flares into an aggressive metastatic disease.
"You can see where, if one ovary is cancerous, it is almost unrecognizable until an instantaneous moment, when it explodes into exponential growth," Conejo-Garcia said. "The key to this moment, our evidence suggests, is in the phenotypic changes taking place in the dendritic cells that are part of the tumor microenvironment."
In healthy tissue, dendritic cells function as sort of alarm system to alert the adaptive part of the immune system to potential threats. They work as antigen-presenting cells, offering foreign or disease-causing molecules (called antigen) to the white blood cells that can then respond to an infection or, in this case, tumorous growths. Amid the ovarian cancer microenvironment, dendritic cells also induce the immune system to attack tumor cells and inhibit their growth.
Until, that is, dendritic cells seem to switch sides.
"We see a change in the dendritic cells themselves, which allows tumors to progress to terminal disease in a very short time," Conejo-Garcia said. "Interestingly, the tumors themselves are still immunogenic—they could still otherwise elicit an immune response—it is just that the dendritic cells are actively suppressing the involvement of other anti-tumor immune cells; primarily T cells."
Conejo-Garcia and his colleagues believe that their findings offer a twist on the emerging theory of "cancer immunoeditting." The immunoeditting hypothesis suggests that the immune system actively "edits" tumor cells to eliminate antigens that are recognized by immune cells, keeping the cancer at bay before it becomes symptomatic. All symptomatic tumors, therefore, represent a failure of the immune system, where tumors lose their immunogenicity—their ability to trigger and be recognized by our immune system.
The researchers found that that depleting dendritic cells early on accelerating tumor expansion, while removing dendritic cells later on actually delayed the tumor's progression. According to Conejo-Garcia, their findings suggest it is a change in the immune system itself, specifically the dendritic cells, and not primarily any loss of immunogenicity on the part of the tumor.
"It is almost as if anti-tumor T cells become exhausted, they can no longer keep up the effort," Conejo-Garcia said. "Still, our findings suggest that the enduring activity of these T cells would allow us to control metastatic ovarian cancer by targeting the dendritic cells that actively prevent their anti-tumor functions."
In fact, Conejo-Garcia and his colleagues have already developed a strategy to reprogram traitorous dendritic cells. In a an upcoming edition of the journal Cancer Research, available online now, the researchers demonstrate how synthetic RNA molecules can be used to win back the allegiance of dendritic cells and restore their ability to stimulate tumor suppression.
Funding for this research was provided through grants from the National Cancer Institute and the Department of Defense.
The lead author of the study is Uciane K. Scarlett, Ph.D., a staff scientist in the Conejo-Garcia laboratory. Wistar co-authors also include Melanie R. Rutkowski, Ph.D. and Ximena Escovar-Fadul. Co-authors from Darmouth Medical School include Adam M. Rauwerdink, Ph.D., Jennifer Fields, Jason Baird, Juan R. Cubillos-Ruiz, Ph.D. (currently at Harvard University), Ana C. Jacobs, Jorge L. Gonzalez, M.D., John Weaver, Ph.D., and Steven Fiering, Ph.D.
Greg Lester | EurekAlert!
Cancer diagnosis: no more needles?
25.05.2018 | Christian-Albrechts-Universität zu Kiel
Less is more? Gene switch for healthy aging found
25.05.2018 | Leibniz-Institut für Alternsforschung - Fritz-Lipmann-Institut e.V. (FLI)
The more electronics steer, accelerate and brake cars, the more important it is to protect them against cyber-attacks. That is why 15 partners from industry and academia will work together over the next three years on new approaches to IT security in self-driving cars. The joint project goes by the name Security For Connected, Autonomous Cars (SecForCARs) and has funding of €7.2 million from the German Federal Ministry of Education and Research. Infineon is leading the project.
Vehicles already offer diverse communication interfaces and more and more automated functions, such as distance and lane-keeping assist systems. At the same...
A research team led by physicists at the Technical University of Munich (TUM) has developed molecular nanoswitches that can be toggled between two structurally different states using an applied voltage. They can serve as the basis for a pioneering class of devices that could replace silicon-based components with organic molecules.
The development of new electronic technologies drives the incessant reduction of functional component sizes. In the context of an international collaborative...
At the LASYS 2018, from June 5th to 7th, the Laser Zentrum Hannover e.V. (LZH) will be showcasing processes for the laser material processing of tomorrow in hall 4 at stand 4E75. With blown bomb shells the LZH will present first results of a research project on civil security.
At this year's LASYS, the LZH will exhibit light-based processes such as cutting, welding, ablation and structuring as well as additive manufacturing for...
There are videos on the internet that can make one marvel at technology. For example, a smartphone is casually bent around the arm or a thin-film display is rolled in all directions and with almost every diameter. From the user's point of view, this looks fantastic. From a professional point of view, however, the question arises: Is that already possible?
At Display Week 2018, scientists from the Fraunhofer Institute for Applied Polymer Research IAP will be demonstrating today’s technological possibilities and...
So-called quantum many-body scars allow quantum systems to stay out of equilibrium much longer, explaining experiment | Study published in Nature Physics
Recently, researchers from Harvard and MIT succeeded in trapping a record 53 atoms and individually controlling their quantum state, realizing what is called a...
25.05.2018 | Event News
02.05.2018 | Event News
13.04.2018 | Event News
25.05.2018 | Event News
25.05.2018 | Machine Engineering
25.05.2018 | Life Sciences