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 killer cells from the body's immune system towards sarcomas. The killer cells 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 clinical trials 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 cancer 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 tumor 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 tumor cells allow the killer cells to distinguish cancer cells from healthy cells.
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 cancer immunotherapy, 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."
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