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18Jul 2019

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Possible new approach to immune-resistant cancer cells

Immunotherapy stimulates the patient's immune system to fight cancer. Despite promising results, however, tumor cells are not always sensitive to this treatment. Researchers at the Netherlands Cancer Institute under the supervision of Prof. Daniel Peeper have identified a number of genes in tumor cells that are involved in therapy resistance, using CRISPR/Cas9 technology. By inactivating these genes, the cancer cells can be made much more sensitive to immunotherapy.
An article about this was on July 11 in the renowned scientific journal Cell.

Resistance to immunotherapy
A patient's immune system plays an important role in fighting cancer cells. Specialized immune cells (white blood cells called T cells) can often recognize and kill the tumor. However, there are tumor cells that somehow manage to counteract these immune cells and even become resistant to them. These cells are then free to continue dividing.

Tumors have ways to bypass the immune system, such as by producing certain proteins on the outside of the cell that inhibit the action of T cells. However, with the help of so-called checkpoint inhibitors, these inhibitory proteins can be blocked so that T cells can function optimally again and eliminate the tumor. This has made immunotherapy a recent breakthrough in combating various forms of cancer; some patients even remain cancer-free for a long time.

Unfortunately, although this treatment works well for a certain group of patients, many tumors are resistant to immunotherapy. A different strategy is needed to use immunotherapy on patients with resistant tumors.

How do you make tumors more sensitive to T cells?
At the Netherlands Cancer Institute, PhD student David Vredevoogd and postdoc Thomas Kuilman from Daniel Peeper's group researched making tumors more sensitive to T cells. Previous research has shown that some tumors become resistant to immunotherapy by bypassing a cell-killing molecule secreted by the T-cell: interferon gamma. Peeper: "We wondered whether there are other resistance mechanisms and, more importantly, whether we can make those unruly tumor cells susceptible to immunotherapy again with a new intervention."

To answer this question, the researchers used CRISPR/Cas9 technology. This relatively new and powerful technology makes it possible, in principle, to inactivate each of the roughly 20,000 genes in a cell and then to study its role in a given process. Researcher David Vredevoogd: "In this case, we have identified several specific genes in a large CRISPR experiment with millions of tumor cells which, if made inactive, make cancer cells a lot more sensitive to T cells."

Balance swings to tumor cell death
One of the genes that appears to be involved in tumor resistance to T cells is TRAF2. This gene determines how tumor cells respond to Tumor Necrosis Factor (TNF). TNF is a molecule that, like interferon-gamma, is secreted by activated T cells. Because it emits different signals, TNF can both stimulate and inhibit tumor cells. The TRAF2 gene contributes to the stimulation of tumor cells. Postdoc Thomas Kuilman: "We thought that if we specifically inactivated TRAF2, only the tumor-inhibiting effect of TNF would remain and the balance would swing to tumor cell death. And that is exactly what we saw: when we disabled the TRAF2 gene, tumor cells in a culture container became much more sensitive to even a very low concentration of TNF. Mice with resistant tumors also responded better to immunotherapy."

CRISPR is an excellent technology for laboratory use, but it cannot yet be used for the treatment of cancer patients. Vredevoogd: "We have therefore started looking for an alternative method to inhibit TRAF2. After some research in the literature, we found an antibody that leads to the breakdown of TRAF2. We were able to demonstrate in the laboratory that this antibody does indeed make tumor cells more sensitive to TNF secreted by T cells."

Peeper: "With this research, we demonstrated in our lab that tumors can be made more sensitive to immunotherapy by inhibiting the TRAF2 gene. Our next goal is to improve the effectiveness of the antibodies that can degrade TRAF2, and ultimately to use them in the treatment of tumors that do not respond well to immunotherapy."


David Vredevoogd*, Thomas Kuilman*, et al. "Augmenting immunotherapy impact by lowering the tumor TNF cytotoxicity threshold". Cell advanced online publication July 11, 2019.

This research was funded by the Dutch Cancer Society (KWF), the European Research Council and the Netherlands Organization for Scientific Research (NWO).

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