Why not every cancer patient responds to immunotherapy? This is the question that researcher Daniel Pepper seeks to answer. His research group is trying to identify the genes that play a role in resistance to immunotherapy. In today’s cover post in . format Medicine Cell ReportsThey describe an important factor behind this treatment resistance, and a possible way to combat it.
Immunotherapy takes the brakes off the body’s immune system, as it were, and stimulates it to destroy cancerous cells. The results can be quite amazing, even in patients with severe tumors.”
Daniel Pepper, Group Leader, Netherlands Cancer Institute
Unfortunately, many tumors do not respond well to immunotherapy. why is that? Can we circumvent this problem?
Cause of treatment resistance
“Because immunotherapies work amazingly well in some patients, we and fellow researchers around the world are looking for ways to make these treatments more effective and widely applicable.” Cancer resistance to immunotherapy manifests itself in several ways. “Some patients do not respond well to treatment from the start. In other cases, treatment appears to be successful at first, but loses its effect over time.”
The cause of resistance can be found in the absence or decreased activity of the important immune cells that can destroy cancer cells: T cells. Some tumors do not appear to contain any T cells, while others contain T cells with little activity. The last problem could be because of what we call Checkpoints in T cells, which can be effectively neutralized by the corresponding inhibitors. Some tumors also cause a battle of their own, making them insensitive to T cells. “And now we’ve discovered a mechanism behind this,” Bieber says.
Treatment resistance is a common phenomenon in cancer treatment. “It’s something we’ve been aware of for a very long time, unfortunately. With chemotherapy, for example, but also with precise drugs that target cancer cells. A tumor tends to respond very well at first and shrink, but often resumes its growth later.” “
Since treatment resistance is an ongoing problem in oncology, Bieber predicted that immunotherapy would be no exception. “It was about ten years ago, when the first studies on immunotherapy were published, and they showed promising results,” he recalls. It is clear that immunotherapy is a game changer. Anticipating a lot of trouble with treatment resistance later, however, he decided to refocus his lab to investigate the problem.
We already have a good understanding of how our immune system protects us from cancer. All cells in our bodies constantly show that our immune system is healthy. T cells are like radars in this process: if they detect any abnormal protein fragments (antigens) on the cell surface, they destroy the cell. These antigens indicate that a particular cell has been infected with bacteria or viruses, or that the cell has turned into a cancerous cell. But this innovative detection system does not always work perfectly. One possible reason is that cancer cells no longer display antigens on their surfaces. The immune system has developed a way around this: Natural killer cells (natural killer cells) can destroy these neglected tumor cells, as long as they receive the appropriate signals.
Some cancer cells have managed to get around this reserve immune radar as well, enabling them to multiply. Three postdoctoral researchers from Peepers’ group, Zhengkui Zhang, Xiangjun Kong and Maarten Ligtenberg, used functional genome-wide screens to learn why cancer cells are sometimes able to resist destruction by both T cells and natural killer cells. “This is a powerful and advanced technology with which we can efficiently investigate any of our 25,000 genes that play a role in this process.”
The researchers cultured cancer cells in their lab, turning off one gene per cell at a time using the CRISPR/Cas9 technology. Then they treated the cancer cells with T cells or natural killer cells to analyze genes involved in resistance against immune cells. This revealed three genes from the same family. Peeping: “If a screen leads us to a complete genetic family, we know that they are usually well-intentioned He hits. In fact, when we turned off these genes – including RNF31 – cancer cells were destroyed more efficiently by T cells and natural killer cells.”
“Fortunately, a tool compound to block RNF31 has already been developed in a laboratory in Japan,” explains Bieber. “This helped us demonstrate that treatment with this inhibitor makes cells more sensitive to immune cells. But we also found something else that was important. As mentioned, tumors often circumvent the T-cell detection system by stopping the presentation of antigens on their cells’ surface. When we made a mixture of Cancer cells that did, and cells that did not, presented the T-cell antigen – which typically occurs in tumors – we found that inhibiting RNF31 also increased the sensitivity of T cells to cancer cells that were invisible to tumor immune cells. spectator to amplify the effect of the treatment.”
Unfortunately, this inhibitor does not have the necessary molecular properties for patient use. If it is to be developed into a usable drug, like any other new drug, it will need to be tested to ensure that it will not harm healthy cells. Peeping: “We are optimistic about this specificity, because inhibiting RNF31 is only effective if there are immune cells nearby. But this definitely requires further research.”
A few years ago, after publishing their first research on immuno-oncology, Bieber set up a company to improve immunotherapy. “We’ve found many new and promising starting points for improving treatment in my lab. Typically, these kinds of results are published in the hope that a pharmaceutical company will pick them up for further development. But that rarely happens, which is quite a shame.” That’s why Peeper founded the startup Immagene BV in 2020, with colleagues Martin Ligtenberg and Christian Blanc, the Netherlands Cancer Institute, and the Oncode Institute. He is currently working as a consultant for the company. “Developing new treatments is not only a completely different discipline that requires specific expertise, but it also involves significant financial risks. We founded this startup because we really believe in our approach.” The company’s exact goals are confidential, but in general it is developing new drugs for immunotherapy.
blow and shove
Peeper recently received a €2.5 million advanced ERC grant, which he will use to study the other problem of treatment resistance: How can we reactivate inactive T cells in a tumor? “We will address this question with CRISPR/Cas9 screens – but this time we will be screening T cells instead of cancer cells, looking for genes that, when inhibited, reactivate T cells. This will enable us to approach the problem of resistance from two different but complementary angles, our goal The goal is to develop smart combination therapies that simultaneously strike cancer cells and boost immune cells.
Netherlands Cancer Institute
Chang, Z.; , et al. (2022) RNF31 inhibition sensitizes tumors to killing by innate and adaptive immune cells. Medicine Cell Reports. doi.org/10.1016/j.xcrm.2022.100655.