Cutting cancer’s lifeline

A new study in the journal Nature reveals that a small signaling molecule has the ability to cut off the blood supply to tumors. This allows the immune system’s T-cells to indirectly fight cancer.

A tumor is a part of one’s own body that at some point decides to turn on itself and proliferate uncontrollably. A considerable amount of tumor tissue consists of healthy cells: Connective tissue provides mechanical support, while blood vessels supply the cancer with nutrients and oxygen. Without these perfectly healthy cells, called stroma, it would be impossible for any large tumor to survive.

Fighting cancer with immunotherapy

Solid tumors like these usually pose big problems for immunotherapy, which is a key research area at the Max Delbrück Center for Molecular Medicine (MDC). In immunotherapy T-cells, a kind of immune cell, act as “special mobile forces” that patrol the body. After learning to recognize the characteristic signature of cancer cells, they can seek them out and kill them.

This strategy has been successful in initial clinical trials – but usually only against cancer cells swimming in the bloodstream. The stroma of a solid tumor constitutes a physical barrier against the patrolling T-cells, which are additionally weakened by inhibiting signals generated by the tumor.

Two very potent signaling molecules

T-cells produce two molecular messengers – tumor necrosis factor (TNF) and interferon gamma (IFN-γ) – that could play a key role in attacking the stroma. These molecules deliver their signal by docking to receptor proteins residing on the cell surface. Both are known for their ability to slow a tumor’s growth.

TNF destroys the blood vessels of the stroma, and due to its toxic side effects, TNF is used for therapy only in very rare cases. One example is the isolated limb perfusion procedure, where the molecule is administered to a limb clamped off from the main blood flow, but does not enter the circulatory system. The systematic use of interferon gamma, however, is still in its early stages. “There has been little understanding of how IFN-γ works,” says MDC researcher Dr. Thomas Kammertöns. “This is unfortunate, since it’s one of the most powerful weapons that T-cells have to fight viruses or cancer.”

Now Kammertöns is searching for solutions – together with a large team of researchers, including Prof. Thomas Blankenstein, Prof. Hans Schreiber and Christian Friese, at the MDC, the Charité – Universitätsmedizin Berlin and Berlin Institute of Health (BIH). The researchers want to understand how IFN-γ acts on stroma tissue and if its effects can be harnessed for better immunotherapy. Their results appeared in a recent issue of the journal Nature.

Identifying the target

“We knew that IFN-γ attacks the cancer via the tumor microenvironment,” says Kammertöns. “We now wanted to find out exactly which cells are targeted by the signaling molecules.”

The researchers genetically engineered a mouse model that mimicked human cancer. These mice lacked the receptor molecule on the cell surface that is responsible for intercepting IFN-γ molecules and thus were unable to receive the molecule’s message. In the next step, only selected cell types – connective tissue cells, immune cells, blood vessel cells and macrophages – got back the signal from the receptor. This strategy allowed the researchers to narrow down the target of IFN-γ.

In most animals the tumors grew despite IFN-γ treatment. But in mice with blood vessel cells that were susceptible to interferon, the blood vessel shriveled, thus shutting down the supply of oxygen and nutrients and killing the tumors.

A microscopic image of tumor tissue under the influence of TNF (left) and IFN- γ (right). Red blood cells are pictured in a magenta color. TNF bursts the blood vessels and releases large amounts of blood cells, whereas IFN-γ lets vessels retreat. Image: Christian Friese / MDC

Unintended effects

Another experiment showed that the interferon acts not only on tumor stroma, but also interferes with the growth of blood vessels in other parts of the body. “It definitely disrupts fast wound healing,” comments Kammertöns on this unexpected finding, which has relevance beyond tumor therapy.

After strokes or heart attacks, for example, fine capillaries are impaired and are further damaged when the undernourished tissue gets re-supplied with blood. Interferon could potentially disrupt rapid neovascularization after such reperfusion events and delay the healing process.

A microscopic image of blood vessels of the same tumor, before (left) and after being under the influence of IFN-γ (right). Cells of the blood vessels are pictured in red. IFN-γ causes blood vessels to retreat. Image: Christian Friese / MDC

Important for tumor therapy

That caveat aside, the scientists now have a better idea how T-cells might be able to overcome solid tumors. The principal investigator Prof. Thomas Blankenstein summarizes: “Destroying a tumor’s infrastructure is probably more effective than killing individual cancer cells.”

This is where the signaling molecule TNF comes back into play. “The two together – IFN-γ and tumor necrosis factor – are a powerful team,” explains Blankenstein. “TNF bursts tumor blood vessels, thus opening up the tissue, while IFN-γ cuts off the blood supply and keeps the tumor at bay over the long term.”

A cancer therapy sometimes has to act on healthy parts of the body to fight the disease. The challenge is now to make this additional weapon useful in T-cell therapy – and to employ it in a way that maximizes its impact on tumors.

Further information

Thomas Kammertoens1,2, Christian Friese1,2, Ainhoa Arina3, Christian Idel4, Dana Briesemeister1,2, Michael Rothe1,2, Andranik Ivanov5,6, Anna Szymborska2, Giannino Patone2, Severine Kunz2, Daniel Sommermeyer2, Boris Engels2,
 Matthias Leisegang1,2,5, Ana Textor1,2, Hans Joerg Fehling7, Marcus Fruttiger8, Michael Lohoff9, Andreas Herrmann10, Hua Yu10, Ralph Weichselbaum3, Wolfgang Uckert2,5, Norbert Hübner2,6,11, Holger Gerhardt2,5,11, Dieter Beule2,5, Hans Schreiber1,4,5, Thomas Blankenstein1,2,5 (2017): „Tumour ischaemia by interferon-γ resembles physiological blood vessel regression.“ Nature 545, p. 98–102. doi:10.1038/nature22311

1Institute of Immunology, Charité – Universitätsmedizin Berlin, Berlin, Germany. 2Max Delbrück Center for Molecular Medicine, Berlin, Germany. 3Department of Radiation and Cellular Oncology, Ludwig Center for Metastasis Research, The University of Chicago, Chicago, USA. 4Department of Pathology, The University of Chicago, Chicago, USA. 5Berlin Institute of Health, Berlin, Germany. 6Charité - Universitätsmedizin Berlin, Berlin, Germany. 7Institute of Immunology, University Clinics Ulm, Ulm, Germany. 8Institute of Ophthalmology, University College London, London, UK. 9Institute for Medical Microbiology, University of Marburg, Marburg, Germany. 10Beckman Research Institute at the Comprehensive Cancer Center City of Hope, Los Angeles, USA. 11DZHK (German Center for Cardiovascular Research), partner site Berlin, Germany.

Featured image: Colorized scanning electron micrograph of a T cell. Picture: National Institute of Allergy and Infectious Diseases, National Institutes of Health, Lizenz: CC-BY-NC.