Rikard Holmdahl

A long-term dream for cancer research is to be able to help the body's immune system to fight tumors. After many years of work and as a result of basic research, great successes have now come to succeed in activating the body's own T cells to attack tumors. This already has great use in tumor treatment and has given new hope to millions of people. The treatment is aimed at blocking cell molecules on the surface of the T cell which limits this activation, these are called CTLA4 and PD1. This finding stems from studies of autoimmune diseases where they have the opposite effect and treatment is now being developed to stimulate their activation. We want to explore a whole new opportunity to further activate T cells so that they can better attack tumors. We have discovered that oxygen radicals coming from macrophages in the immune system and in the tumor tissue downregulate the activity of T cells. The discovery was made through genetic studies in mice, which were subsequently confirmed in humans, and we could see that a defective gene called Ncf1 reduces the oxygen radical production, leading to more severe autoimmune disease but a strong protection against the development of cancer in mice (malignant melanoma and lung cancer). With this project we want to identify exactly in which cell and with which mechanism the redox control takes place. The aim is then to find new therapeutic possibilities where we can block the dampening effect of oxygen radicals and thereby strengthen the immune system's ability to fight tumors.

A long-term dream for cancer research is to be able to help the body's immune system to fight tumors. After many years of work and as a result of basic research, great successes have now come to succeed in activating the body's own T cells to attack tumors. This already has great use in tumor treatment and has given new hope to millions of people. The treatment is aimed at blocking cell molecules on the surface of the T cell which limits this activation, these are called CTLA4 and PD1. This finding stems from studies of autoimmune diseases where they have the opposite effect and treatment is now being developed to stimulate their activation. We want to explore a whole new opportunity to further activate T cells so that they can better attack tumors. We have discovered that oxygen radicals coming from macrophages in the immune system and in the tumor tissue downregulate the activity of T cells. The discovery was made through genetic studies in mice, which were subsequently confirmed in humans, and we could see that a defective gene called Ncf1 reduces the oxygen radical production, leading to more severe autoimmune disease but a strong protection against the development of cancer in mice (malignant melanoma and lung cancer). With this project we want to identify exactly in which cell and with which mechanism the redox control takes place. The aim is then to find new therapeutic possibilities where we can block the dampening effect of oxygen radicals and thereby strengthen the immune system's ability to fight tumors.

A long-term dream for cancer research is to be able to help the body's immune system to fight tumors. After many years of work and as a result of basic research, great successes have now come to succeed in activating the body's own T cells to attack tumors. This already has great use in tumor treatment and has given new hope to millions of people. The treatment is aimed at blocking cell molecules on the surface of the T cell which limits this activation, these are called CTLA4 and PD1. This finding stems from studies of autoimmune diseases where they have the opposite effect and treatment is now being developed to stimulate their activation. We want to explore a whole new opportunity to further activate T cells so that they can better attack tumors. We have discovered that oxygen radicals coming from macrophages in the immune system and in the tumor tissue downregulate the activity of T cells. The discovery was made through genetic studies in mice, which were subsequently confirmed in humans, and we could see that a defective gene called Ncf1 reduces the oxygen radical production, leading to more severe autoimmune disease but a strong protection against the development of cancer in mice (malignant melanoma and lung cancer). With this project we want to identify exactly in which cell and with which mechanism the redox control takes place. The aim is then to find new therapeutic possibilities where we can block the dampening effect of oxygen radicals and thereby strengthen the immune system's ability to fight tumors.

"Everyone is an expert in different parts of cancer biology, the combination of a common hypothesis and tumor model allows us to approach the problem from different but complementary directions," explains Elias Arnér, professor of biochemistry with a focus on selenium biochemistry. The project, which is supported by the Knut and Alice Wallenberg Foundation, is based on redox biology. Redox, the reduction or oxidation of molecules in the cells, are vital chemical reactions. Upon reduction, electrons are absorbed and, upon oxidation, electrons are emitted. Processes that, among other things, allow us to breathe and which give us and all living energy. But some percent of the oxygen we breathe forms reactive oxygen radicals, ROS, in the cells. These can easily react with the structures and functions of the cells, which in turn can disrupt a balance that is important to prevent disease.  - It has become increasingly clear over the years that redox processes play a major role in the functioning of cells, both in normal, healthy, cells and cancer cells. Different redox processes are important for how cancer develops, but also for how effective different cancer therapies can be. Oxidative stress Radiation and cytostatics often appear to increase oxidation in cancer cells and this is something that is good for a good treatment effect if the researchers' hypothesis is correct. - We believe that an even more effective treatment would be possible with the help of increased levels of free oxygen radicals in the cancer cells, through increased oxidation, while at the same time reducing the levels of these in immune cells. By increasing the oxidation in cancer cells, many of them would die from so-called oxidative stress, while a reduced oxidative stress in the immune system can strengthen its ability to fight the cancer cells. The trick is to gas and brake at the same time. - Oxidative stress depends on many factors, how the cell grows, its metabolism, how it is treated and how high the sugar levels are. Two birds with one stone By inhibiting the enzyme NOX2, which is found only in immune cells and not in cancer cells, the reduction in the immune cell could be increased, which could theoretically provide better protection against cancer. Another way would be to stimulate the transcription factor Nrf2, which also increases the reduction and could make the immune cells function better. - The cancer cells already have a maximum Nrf2 activity, a reduction activity at the top, and thus counteract their own already high levels of oxygen radicals. But there is another way and this is where Elias Arnér's expertise on the harness comes in. Selenium proteins that, among other things, TrxR protect the cells against free oxygen radicals and prevent them from being exposed to oxidative stress. - It is possible to inhibit the enzyme TrxR, or functions of GSH (glutathione) in the cancer cells. If you succeed in inhibiting TrxR you could hit two flies in one blow. It would increase the oxidation in cancer cells and kill them, while we believe that the reduction in normal cells would increase through stimulated activity of Nrf2, thus providing overall protection against cancer. Carefully optimistic The aim of the project is to improve existing cancer treatments and medicines, but also to develop platforms for new drugs. A decisive factor in the work is the specific mouse models and the knowledge about these, and about the redox biology in cancer, that the participating research groups have. - With the help of genetic technology we can remove important enzymes in the redox process and see what happens. We can manipulate both the cancer cells and the host's specific genes. We can also give the mice tumors and then treat them to see which method and combination of modulation of the redox processes is the most effective. The tumor forms that the researchers are working on as a model system are lung cancer and skin cancer. - But we think the principles are pretty general for most cancers. One advantage is that we, through Rolf Kiessling and his group, also have tissue from patients with skin cancer that we can use to see if conclusions and results from the mouse models are also correct in humans. Despite the massive research that is ongoing, cancer diseases continue to be the second most common cause of death after cardiovascular disease in Sweden, among others. But Elias Arnér is cautiously optimistic. - I think we are somewhat on track in this project. In general, we always get a better understanding of how cancer develops and develops, which provides better and better treatment options. Development is constantly advancing and it would be strange if medical developments would stop today. Text Carina Dahlberg Pictures Magnus Bergström Published: 2016