How killer cells take out tumors

June 2, 2017 by Fabio Bergamin
How killer cells take out tumours
Cancer immunotherapy under the microscope: In the center of the image, three killer cells (violet, smaller) attack a cancer cell (violet, larger; leukemia cells are shown here). Credit: Schliemann et al.: Cancer Immunol Res 2015, 3: 547

The use of immunotherapy to treat cancer is celebrating its first successes – but there are still many knowledge gaps in the underlying mechanisms of action. In a study of mice with soft tissue tumors, ETH researchers have now shown how endogenous killer cells track down the tumors with the help of dormant viruses.

The promising drug is known as F8-TNF. When injected into the bloodstream, it lures from the body's immune system towards sarcomas. The killer then destroy the tumors. Researchers from ETH Zurich, led by Professor Dario Neri at the Institute of Pharmaceutical Sciences, developed F8-TNF four years ago. Since then, they have been able to show that it can completely cure sarcomas in mice when combined with a chemotherapeutic agent. Such an effective treatment cannot be achieved by chemotherapy alone or with other therapeutic approaches. Now, a drug closely related to F8-TNF is being tested as part of in humans.

Consisting of two sub-units, the F8-TNF molecule works rather like a store detective: just as a detective tracks down a shoplifter and detains it until the police arrive, the molecule identifies cells using its F8 sub-unit and then uses its TNF part to lure killer cells (cytotoxic T cells). TNF is an immune system messenger.

Implanted into the genome

Much of the molecule's mechanism of action was hitherto unclear, but the scientists in Neri's group have now succeeded in working it out. They wanted to find out how the killer cells recognize the after they are lured to it. Although the messenger TNF alerts the killer cells to the tumor's presence, it does not provide them with a specific tumor identifier.

The scientists discovered that the killer cells called by F8-TNF are guided by proteins from specific dormant viruses (endogenous retroviruses). The genetic blueprint of these viruses has implanted itself into the mouse genome during evolution. In many cancer cells, the viral proteins are brought to life. Fragments of these retroviral proteins on the surface of allow the killer cells to distinguish from .

Immune protection against cancer

In addition, the scientists observed that mice where the sarcomas were cured with F8-TNF rejected tissue later transplanted from various types of tumor. "The mice appeared to have acquired a sort of immune protection against cancer. As it turned out, this protection is also due to the killer cells, which recognize the tumor cells with the help of dormant viral proteins," says Philipp Probst, a doctoral student in Neri's group.

In , the body's immune system is activated in order to combat tumors. In the past, many scientists assumed that the killer cells used modified proteins on the surface of tumor cells as an identifier and a point of attack. Tumors are a degenerate form of body tissue; they are formed as a result of certain genetic mutations in a precursor cell, which can lead to protein modifications. "In some cases, mutated proteins can indeed be the distinguishing criterion," says Neri. "In our paper, however, we confirm that killer cells can also use other distinguishing criteria, namely the presence or absence of retroviral proteins."

Aid to understanding

"Now we cannot only cure sarcomas in mice, but also know the mechanism behind this therapy," says Probst. In the relatively new field of cancer immunotherapy, it is important to understand the underlying mechanisms in order to predict which patients will respond best to which therapy.

Further research will be needed to find out whether the observations in mice also apply to humans, as the human genome is full of gene sequences from dormant viruses. In any case, the knowledge may be useful in the interpretation of clinical trials. The third and final phase clinical trials in humans for the active agent L19-TNF, which is related to F8-TNF, will soon begin in Germany; in the US, applications for such trials are currently being examined by the authorities.

Cancer immunotherapy 100 years ago

More than 100 years ago, New York-based doctor William Coley had already observed that some sarcoma patients recovered spontaneously. These were all patients suffering not only from cancer but also from a bacterial infection. Coley attempted to convert his observation into a therapeutic approach and began to inject sarcoma patients with a cocktail of heat-inactivated bacteria. His experiments were successful and "Coley's toxin" became the therapy of choice for sarcoma patients in the early decades of the 20th century. Although it was later displaced to some extent by radiotherapy and the emerging field of chemotherapy, "Coley's toxin" was still manufactured in Germany until 1990.

In Coley's time, knowledge was not yet advanced enough to understand his cocktail's mechanism of action. From today's perspective, one must assume that the inactivated bacteria triggered an immune response and thus the formation of the messenger TNF. In turn, this messenger activated killer cells that fought the tumor.

Explore further: Designer viruses stimulate the immune system to fight cancer

More information: Philipp Probst et al. Sarcoma eradication by doxorubicin and targeted TNF relies upon CD8+ T cell recognition of a retroviral antigen, Cancer Research (2017). DOI: 10.1158/0008-5472.can-16-2946

Related Stories

Designer viruses stimulate the immune system to fight cancer

May 26, 2017
Swiss scientists from the University of Geneva (UNIGE), Switzerland, and the University of Basel have created artificial viruses that can target cancer. These designer viruses alert the immune system and cause it to send ...

Scientists light the way for immune system to attack cancer

May 15, 2017
The science behind harnessing the immune system to fight cancer is complicated, but a University of Rochester Medical Center laboratory discovered a simple, practical way to use light and optics to steer killer immune cells ...

New anti-cancer strategy mobilizes both innate and adaptive immune response

July 1, 2016
Though a variety of immunotherapy-based strategies are being used against cancer, they are often hindered by the inability of the immune response to enter the immunosuppressive tumor microenvironment and to effectively mount ...

Killer T cells recognize cancer in pre-clinical tumors, but are silenced as tumor develops

August 9, 2016
One of the challenges for developing truly successful immunotherapies is that cancer is a wily foe for the immune system. Tumors have multiple lines of defense against our immune cells' attempts to attack them. Although our ...

How to rescue the immune system: Study could lead to novel therapy for cancer

February 26, 2012
In a study published in Nature Medicine, Loyola researchers report on a promising new technique that potentially could turn immune system killer T cells into more effective weapons against infections and possibly cancer.

Researchers take step toward eliminating cancer recurrence

September 1, 2016
Scientists from the United States have made an important step toward eliminating cancer recurrence by combining immunotherapy with chemotherapy. Specifically, they found that chemotherapy alone leads to two types of dormant ...

Recommended for you

Comparison of screening recommendations indicates annual mammography

August 21, 2017
When to initiate screening for breast cancer, how often to screen, and how long to screen are questions that continue to spark emotional debates. A new study compares the number of deaths that might be prevented as a result ...

Vitamin C may encourage blood cancer stem cells to die

August 17, 2017
Vitamin C may "tell" faulty stem cells in the bone marrow to mature and die normally, instead of multiplying to cause blood cancers. This is the finding of a study led by researchers from Perlmutter Cancer Center at NYU Langone ...

Outdoor light at night linked with increased breast cancer risk in women

August 17, 2017
Women who live in areas with higher levels of outdoor light at night may be at higher risk for breast cancer than those living in areas with lower levels, according to a large long-term study from Harvard T.H. Chan School ...

Scientists develop novel immunotherapy technology for prostate cancer

August 17, 2017
A study led by scientists at The Wistar Institute describes a novel immunotherapeutic strategy for the treatment of cancer based on the use of synthetic DNA to directly encode protective antibodies against a cancer specific ...

Scientists develop blood test that spots tumor-derived DNA in people with early-stage cancers

August 16, 2017
In a bid to detect cancers early and in a noninvasive way, scientists at the Johns Hopkins Kimmel Cancer Center report they have developed a test that spots tiny amounts of cancer-specific DNA in blood and have used it to ...

Toxic formaldehyde is produced inside our own cells, scientists discover

August 16, 2017
New research has revealed that some of the toxin formaldehyde in our bodies does not come from our environment - it is a by-product of an essential reaction inside our own cells. This could provide new targets for developing ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.