Cell breakthrough: research reveals a new way to enhance the efficacy of immunotherapy and fight against immune resistant cancer cells

August 17, 2019 / BIOON / - immunotherapy stimulates the patient's immune system against cancer However, despite good results, tumor cells are not always sensitive to this treatment Under the supervision of Professor Daniel peeper, researchers from the Netherlands Cancer Institute found some genes related to drug resistance in tumor cells by using CRISPR / cas9 technology By inactivating these genes, cancer cells can become more sensitive to immunotherapy Relevant research results were recently published in cell The immune system of patients with tolerance to immunotherapy plays an important role in the fight against cancer cells Special immune cells (white blood cells called T cells) recognize and kill tumors However, some tumor cells try to fight against these immune cells in some way, and even become resistant to them Then the cells are free to continue to divide Image source: cell tumors have ways to bypass the immune system, such as by producing proteins outside the cell to inhibit the activity of T cells However, with the help of so-called checkpoint inhibitors, these inhibitory proteins can be blocked, allowing T cells to perform their best function again and eliminate tumors This makes immunotherapy the latest breakthrough in the fight against all kinds of cancer; some patients don't even have cancer for a long time Unfortunately, although this treatment works well for certain patients, many tumors are resistant to immunotherapy A different strategy is needed to use immunotherapy in patients with drug-resistant tumors How to make tumor more sensitive to T cells? At the Dutch cancer institute, Dr David vredevoogd and postdoctoral Thomas kuilman of the Daniel peeper team studied how to make tumors more sensitive to T cells Previous studies have shown that some tumors are resistant to immunotherapy by bypassing interferon gamma, a cytotoxic molecule secreted by T cells "We want to know if there are other mechanisms of resistance, and more importantly, if we can use new interventions to make those tumor cells that are difficult to control sensitive to immunotherapy again," peeper said "CRISPR / cas9 was used to answer this question In theory, this relatively new and powerful technology can inactivate each of about 20000 genes in a cell, and then study its role in a specific process Researcher David vredevoogd said: "in this case, we have identified several specific genes in a large CRISPR experiment, which uses millions of tumor cells If these cells are inactive, they will make cancer cells more sensitive to T cells "One of the genes that seem to be involved in tumor cell death due to imbalance is TRAF2 This gene determines the response of tumor cells to tumor necrosis factor (TNF) TNF is a molecule that, like interferon - γ, is secreted by activated T cells Because TNF sends different signals, it can stimulate and inhibit tumor cells TRAF2 gene is involved in stimulating tumor cells Postdoctoral Thomas kuilman: "we believe that if we specifically inactivate TRAF2, the tumor inhibitory effect of TNF will remain unchanged, and the balance will turn to tumor cell death This is what we see: when we disable the TRAF2 gene, the tumor cells in the culture vessel become more sensitive to very low concentrations of TNF Mice with drug-resistant tumors also responded better to immunotherapy "CRISPR in the future is an excellent technology for the laboratory, but it can not be used for the treatment of cancer patients at present Vredevoogd: "so we've started looking for alternatives to inhibit TRAF2 On the basis of literature research, we found an antibody that leads to the decomposition of TRAF2 We can prove in the laboratory that this antibody does make tumor cells more sensitive to TNF secreted by T cells "Peeper:" through this study, we have proved in the laboratory that tumor can be more sensitive to immunotherapy by inhibiting TRAF2 gene Our next goal is to improve the effectiveness of antibodies that degrade TRAF2 and eventually use them in the treatment of tumors that do not respond well to immunotherapy "Reference: Daniel S peeper et al August immunology impact by lowering tumor TNF cyclocity threshold Cell Doi: https://doi.org/10.1016/j.cell.2019.06.014