Science Sub-journal: To make cold tumors hot, simply suppress ingenuating the gene, can greatly enhance the effectiveness of PD-1 therapy.

In fact, there are two types of tumors: cold tumor and hot tumor. They refer to tumors with immune origin (hot tumor) and tumor without immune source (cold tumor).Hot tumor: many immune cells have gathered near the tumor tissue, and the immune cells have fought with the cancer cells. However, the battle is still hot.cold tumor: compared with hot tumor, there are no or only a few immune cells in tumor tissue. Here, immune cells have never fought with cancer cells, and the battlefield has not even been ignited.immunocheckpoint inhibitors developed based on immune checkpoints, such as PD-1 inhibitors, PD-L1 inhibitors, etc., have played a very good role in skin melanoma, non-small cell lung cancer, kidney cancer, bladder cancer, head and neck cancer and Hodgkin's lymphoma.however, immune checkpoint inhibitors are more effective for so-called "hot tumors".because there are already immune cells, especially T cells, in thermal tumors, but these T cells have been bound and bound by tumor cells. Immune checkpoint inhibitors can relieve the braking effect of tumor on T cells. These liberated T cells can quickly mobilize and kill tumor cells.for "cold tumor", immune cells are difficult to recognize and kill, and immune checkpoint inhibitors are difficult to play a role. So, is there a way to transform "cold tumor" into "hot tumor"? Recently, ze'ev a. Ronai of Sanford Burnham prebys Institute of medical discovery published a research paper entitled "Prmt5 control of CGAs / sting and nlrc5 pathways define melanoma response to antitumor immunity" in Science Translational Medicine.this study confirmed that there is a negative correlation between Prmt5 gene function and anti-tumor immunity. By pharmacological or genetic methods, inhibition of Prmt5 gene and combination of immunocheckpoint therapy can significantly inhibit the growth of melanoma and improve the therapeutic effect of cancer.these findings provide the basis for clinical trials of immunocheckpoint therapy combined with Prmt5 inhibitors to enhance anti-tumor immune response.the emergence of tumor immunotherapy based on immune checkpoint has completely changed the treatment methods of some cancers. The 2018 Nobel Prize in physiology or medicine was awarded to Japanese scientist Ben Shuyou and American scientist James Allison, in recognition of their pioneering immunocheckpoint cancer therapy and their outstanding contributions to cancer treatment.for some patients with advanced melanoma, immune checkpoint therapy can extend their survival time from several months to several years, which has to be said to be a great achievement.however, 40% of melanoma patients still do not respond to immune checkpoint therapy, which is a cold tumor. Scientists have been trying to find new methods to turn cold tumors that are not responsive to immunotherapy into hot ones, so as to benefit more cancer patients.turning the "cold" tumor into "hot" tumor in this study, the team used a mouse model of melanoma to verify the combination of Prmt5 inhibitor and PD-1 inhibitor.under normal circumstances, mice that did not respond to PD-1 inhibitors had smaller tumor size and longer survival time after receiving Prmt5 inhibitors.the slow reaction cold tumor was successfully transformed into a hot tumor, which enhanced the ability of immune system to attack tumor.this effect can be achieved by using inhibitors to inhibit Prmt5 or down regulating Prmt5 expression by shRNA.the development of immunosuppressive checkpoint inhibitors is an important step in the treatment of advanced melanoma, which can make more than half of patients with advanced melanoma live more than 5 years. however, a considerable number of patients are still resistant to this treatment, so we continue to develop new treatments to relieve this resistance. in this study, the team identified two cellular signaling pathways that were inhibited by Prmt5, allowing the tumor to escape immune system surveillance. one pathway is responsible for antigen presentation, and the other pathway controls cytokine production and innate immunity. these pathways jointly determine the ability and degree of tumor escape from the immune system. therefore, the inhibition of Prmt5 can make the tumors that are not detected by the immune system (no response to immune checkpoint treatment) become immune attack and sensitive. this finding can also be extended to other tumor treatments that are not responsive to immunocheckpoint therapy. in general, the study found and confirmed that Prmt5 plays an important regulatory role in tumor through two different signaling pathways, which helps tumor cells escape immune, leading to immune checkpoint therapy failing to work. based on this finding, inhibition of Prmt5 may enhance the anti-tumor immune response and turn cold tumor resistant to immunotherapy into hot tumor, thus improving the therapeutic effect of immunocheckpoint therapy and prolonging the survival time of cancer patients. paper links: