Great contribution in 2019: cancer immunotherapy heavyweight research results!

Time is always fleeting In an instant, 2019 is coming to an end In the coming year, what important research achievements have scientists made in the field of cancer immunotherapy research? In this paper, the editor collates the relevant important research results and shares them with you! Image source: Emory University [1] immunology: clarifying the mechanism of T cell "depletion" is expected to improve cancer immunotherapy doi: 10.1016/j.immunity.2019.11.002 Recently, in a research report published in the international journal immunology, scientists from Emory University provided new clues on how to improve cancer immunotherapy by studying the "exhausted" immune cells caused by chronic virus infection; in the article, researchers studied the exhausted CD8 in mice T cell research, when there is persistent virus infection or cancer, CD8 T cell will lose the ability to resist the disease, at the same time, it will show the inhibitory checkpoint protein on its surface, such as PD-1, PD-1 can be targeted by cancer immunotherapy drugs, such as pemmab and navumab, which can promote CD8 T cells regain the ability to attack and kill infected cells and cancer At present, these drugs have been approved by FDA to treat many types of cancer However, some tumors do not respond to them Research on depleted CD8 T cells can help understand how to use their own immune system to resist cancer or chronic infection In previous studies, researchers have found that depleted cells are not all the same, and the diversity of depleted T cell pools may help explain the variability of the body's response to cancer immunotherapy; in particular, researchers have observed a class of stem cells Like cells, which can continuously proliferate to respond to PD-1 blockers, and a more differentiated depleted cell population will remain inactive These stem cell like cells can maintain depleted T cell populations, but will not kill virus infected cells or tumor cells 【2】 Immunity: oncolytic virus expressing leptin promotes T cells to clear tumors, which is expected to develop a new cancer immunotherapy doi: 10.1016/j.immunity.2019.07.003 although cytotoxic T cells use many different effective ways to kill infected or cancerous cells, they usually fail to effectively clear solid tumors In some cases, T cells simply cannot enter the dense tumor tissue In other cases, T cells suffer from failure and cannot play an effective role By reducing the co-use of oxygen and nutrients in tissues, tumors greatly change their local environment, resulting in T cell metabolism deficiency and preventing these cells from functioning T cell reprogramming to increase glucose uptake or maintain mitochondrial function can enhance antitumor response In a new study, in order to maintain anti-tumor T cells in a bad tumor microenvironment, researchers from the University of Pittsburgh in the United States cleverly chose the cytokine leptin to reprogram T cell metabolism, and the relevant research results were published in the Journal of Immunology; leptin is known to play a major role in human metabolism and obesity, but this protein has been largely Tumor immunologists ignored Using the steady-state expression of leptin receptor in T cells and the up-regulation of leptin receptor expression in tumor infiltrating T cells, these researchers first confirmed that exogenous leptin can enhance the metabolism and proliferation of T cells By injecting oncolytic vaccinia virus (VACV), a oncolytic virus, directly into the tumor of mice to achieve local delivery of leptin, the recruitment of T cells into the tumor can be improved and the mitochondrial content of T cells can be increased 【3】 Cell: scientists successfully selected the key target of developing new cancer immunotherapy doi: 10.1016/j.cell.2019.07.044 In the past 10 years, immunotherapy has brought revolutionary changes to cancer treatment However, many tumors have not responded to these new therapies Recently, scientists from Yale University have identified a number of new candidate genes by studying the whole genome screening of 20000 human genes in T cells, which can promote the immune system to attack multiple types of tumors The results are published in the international journal Cell Researcher Sidi Professor Chen said that immunotherapy is not effective for all patients, and about 70% - 80% of the patients have no response to the therapy; then why don't we study the gene level to analyze which genes are mainly responsible for tumor growth, and at the same time find the potential target of developing new cancer therapy; many immunotherapies are developed based on the inhibition of PD1 gene, PD-1 can inhibit T cell mobilization and The ability to attack tumor cells, these therapies significantly improve the survival rate of patients with various types of cancer, such as melanoma and lung cancer, etc., but even in these cancers, only 30% - 40% of patients can respond to immunotherapy, for most types of cancer, the response rate of patients is less than 20%, some malignant tumors The response rate of patients was even less than 10% 【4】 Great progress of nature! A new "don't eat me" signal on cancer cells has been found A new immunotherapy is coming Doi: 10.1038/s41586-019-1456-0 a few days ago, in a research report published in the international journal Nature, researchers from Stanford University School of Medicine found a new signal that cancer seems to be able to use to evade detection and destruction of the immune system Scientists have shown that blocking this signal in mice implanted with human cancer allows immune cells to attack cancer Blocking other "don't eat me" signals has become the basis for other possible cancer therapies In general, immune cells called macrophages detect cancer cells and then phagocytize them In recent years, researchers have found that proteins on the surface of cells can tell macrophages not to eat and destroy them This can help normal cells prevent the immune system from attacking them, but cancer cells use these "don't eat me" signals to evade the immune system Previously, researchers found that cancer cells use PD-L1 and CD47 to protect themselves from immune cells Antibodies that block CD47 are in clinical trials Cancer therapy targeting at PD-L1 or PDL1 receptor is being used clinically Researchers at Stanford University now report that they have found a protein called CD24 that can also be used as a "don't eat me" signal and used by cancer cells to protect themselves 【5】 Nature Nature Medicine: a new breakthrough in cancer immunotherapy! Engineered bacteria act as a Trojan horse to effectively inhibit tumor progression! Doi: 10.1038/s41591-019-0498-z doi: 10.1038/nature18930 at present, the new field of synthetic biology design of new biological components and systems is completely changing the progress of medicine, through the inheritance of living cells By programming, researchers can develop an engineering system of intelligent perception and response to a variety of environments Compared with the current molecular based therapy, this new system can produce more specific and effective solutions In the past decade, cancer immunotherapy (i.e using the patients' own immune defense to resist cancer) has brought revolutionary changes to cancer treatment, but only a small number of solid tumors will respond to this treatment, and systematic treatment usually brings obvious side effects to patients, and designs an effective anti-tumor induction in solid tumors The method of immune response without systemic toxicity may be a great challenge for researchers at present Recently, an international magazine Nature In the Research Report on medicine, cancer researchers from Columbia University overcome the above problems through research By engineering modification of a non pathogenic bacteria, the researchers can plant it in solid tumors, and safely provide effective immunotherapy The engineered non pathogenic bacteria can play a "Trojan horse" to help resist Tumor The researchers pointed out that this new therapy can not only make the tumor completely subside in the model group of lymphoma mice, but also effectively control the tumor lesions in the distal part of the body without injection Photo source: cell, 2019, Doi: 10.1016/j.cell.2019.07.019 [6] cell: manipulation of interferon signal is expected to make cancer immunotherapy effective doi: 10.1016/j.cell.2019.07.019 in a new study, researchers from the University of Pennsylvania in the United States found that a key signaling pathway that can tell the immune system to resist cancer can also be used by cancer cells to inhibit the immune system They said this increased understanding could serve as a biomarker to help predict which patients might respond to immunotherapy They also showed how changing this balance could have a potential impact on the treatment itself, because blocking this signal in cancer cells helps immune cells resist tumors in a variety of preclinical cancer models, the results of which are published in the journal Cell The study focused on interferon (IFN) signaling pathway Interferon usually helps activate the immune system to protect cells from viruses, so it's named because they actually interfere with the ability of the virus to spread However, interferon can also inhibit the immune system Dr Andy J Minn, the researcher, said that this paradoxical effect has emerged in other diseases such as chronic viral infection, but our study shows how cancer cells can use the inhibitory properties of interferon to interfere with cancer immunotherapy 【7】 Nature: great discovery! Targeted iron death is expected to enhance the efficacy of immunotherapy doi: 10.1038/s41586-019-1170-y in a new study, researchers from the University of Michigan and Cayman chemical company in the United States studied a little-known type of cell death, namely iron death They found that iron death occurs in tumor cells and plays a role in cancer immunity, suggesting that targeting this pathway has the potential to make the most popular cancer treatment, immunotherapy, more effective The results were published in the journal Nature "Iron death was defined before, but it was not known to be related to cancer cell death or immune cells," the researchers said This will open up a huge window for scientists to explore The researchers found that when immunotherapy increased the activity of T cells, it increased the level of lipid oxide in tumor cells, leading to iron death Based on studies of mice and human cancer cells, increased iron death can make immunotherapy more effective in killing cancer 【8】 Nature weighs heavily: pre inhibition of TNF can significantly enhance the efficacy of PD-1 and CTLA-4 combined immunotherapy and reduce the side effects Doi: 10.1038/s41586-019-1162-y a cooperative experimental study led by researchers from CIMA and Navarra clinical University proposed a new method for cancer treatment, that is, to use combined immunotherapy in animal models to solve the problems of efficacy and toxicity This clinical strategy includes blocking a protein involved in the regulation of the immune system (called tumor necrosis factor, TNF), and combining immunotherapy (inhibiting other "slow down" immune response proteins such as PD-1 and CTLA-4) Relevant research results were published in the journal natrue recently In this study, we found that the immunoregulatory function of tumor necrosis factor is dispensable, even to some extent, for this combined immunity, the researchers said