Nature weighs heavily: Remolding regulatory T cells to improve the therapeutic effect of cancer

May 17, 2019 / BIOON / - although the use of the immune system to fight cancer has made significant progress in the fight against certain types of tumors, they are still ineffective for most cancer patients A new study by the center for immunology and inflammatory diseases (CIID) at Massachusetts General Hospital describes a way to reprogram regulatory T cells that normally inhibit immune responses to inflammatory cells, not only allowing but also enhancing antitumor immune responses Relevant research results were published in nature recently Photo source: nature "many patients' tumors do not respond to immunotherapy - such as immunosuppression - because of the lack of inflammation in tumor tissue, which is necessary for these therapies to work," said Thorsten mempel, MD, MGH CIID, senior author of the nature paper "Our research shows that reprogrammed Treg cells provide exactly the type of inflammation that is lacking In fact, we found in mice that reprogramming tumor infiltrating Treg cells to secrete inflammatory cytokines made previously unresponsive tumors highly sensitive to PD-1 blockade "The focus of MGH research is CBM complex, a large protein cluster in immune cells, which helps regulate their activation, proliferation and function Recent studies have revealed a key role of CBM complex in lymphocyte function It has been known that deletion of one of the three key proteins (CARMA1) will reduce the function of effector T cells The team tested the effect of CARMA1 deletion on Treg cells Their experiments showed that targeting CBM complex (either by deleting one or two copies of CARMA1 gene of Treg cells or by inhibiting another component of MALT1 complex with drugs) can cause Treg cells to secrete immune stimulating cytokine IFN γ It can selectively regulate the function of Treg in tumor and avoid the risk of autoimmune diseases caused by systemic Treg deficiency CBM targeting leads to inflammation of tumor tissue and increased infiltration of cytotoxic CD8 T cells and natural killer cells But it only reduced the tumor growth rate of melanoma and colon cancer mice model, because the activity of these immune cells is still limited by the immunocheckpoint protein PD-1 However, blocking the activity of PD-1 with antibodies can eliminate tumors inflamed by anti CBM therapy "Treg cells are more 'self reactive', which means they respond to our own 'self' tissue antigens," explains mempel, an associate professor of medicine at Harvard Medical School "By reprogramming Treg cells in tumor tissue, we created a local inflammatory autoimmune response to prepare for immunotherapy of tumors So, instead of trying to get rid of Treg cells, we can now use their self reactivity to treat cancer Dr Mauro di Pilato, a researcher at Dr mempel's laboratory and the lead author of the study, added: "now we need to assess whether this approach can also be applied to humans and understand why the cell chambers reprogrammed by targeting CBM complexes are Treg cells in the tumor environment, not elsewhere Reprogramming Treg cells can improve patients' response to immunosuppressive agents, which may increase the number of patients who can be helped with immunosuppressive therapy "Reference: Thorsten R mempel et al Targeting the CBM complex causes Treg cells to prime tumours for immune checkpoint therapy, nature (2019) Doi: 10.1038/s41586-019-1215-2