Release date: 2017-05-04
At present, in the field of cancer immunotherapy, cracking the mystery of drug resistance and expanding the scope of application of such therapies are problems that many scientists are actively solving. A recent study published in the journal Nature found that interferon-gamma (IFN-γ) produced by T cells plays a key role in the treatment: it cuts off the blood supply to the tumor. This achievement provides important clues on how to improve T cell therapy for solid tumor treatment.
In recent years, T cell immunotherapy has brought great hope to cancer patients. These therapies have achieved some initial success in the treatment of blood cancer, however, solid tumor treatment remains a major challenge. On April 26, a study published in the journal Nature entitled "Tumour ischaemia by interferon-γ resembles physiological blood vessel regression" found that the interferon-gamma (interferon-γ, IFN-γ) produced by T cells is The treatment plays a key role: it cuts off the blood supply to the tumor.
The immune system is the most powerful weapon against the disease. So what if you could use the immune system to treat cancer? For a long time, researchers have been working to achieve such therapies, for example, through the development of anti-cancer therapies with immune cells called T cells. At present, the use of T cell immunotherapy for the treatment of blood cancer has been successful in clinical trials. However, such therapies are less effective in responding to solid tumors. Scientists have been trying to solve this problem.
In this latest published study, scientists from the Max Delbrück Center for Molecular Medicine investigated how T cell signaling molecules affect the tumor environment, including connective tissue and blood vessels.
In fact, T cells not only produce tumor necrosis factor (TNF), but also IFN-γ. However, until now, little is known about how IFN-γ works.
Dr. Thomas Kammert?ns, the lead author of the study, said: "Previously, we knew that IFN-γ attacks cancer cells through the tumor microenvironment. Now, we want to figure out which cells are specifically targeted by such signaling molecules."
A microscopic image of blood vessels of the same tumor, before (left) and after being under the influence of IFN-γ (right). Cells of the blood vessels are pictured in red. IFN-γ causes blood vessels to retreat.
Targeting vascular cells
The researchers designed a special transgenic mouse model. Only vascular cells in such mice are susceptible to IFN-γ.
In this mouse model, IFN-γ "pruned back" the blood vessels of the tumor, thus shutting off the oxygen and nutrient supply, thereby killing the tumor. The researchers observed the details of the process in a living mouse by microscope. They found that only vascular cells respond to this signaling molecule. When the researchers target other types of cells with IFN-γ, the tumor will continue to grow.
These findings provide a good explanation for the powerful properties of IFN-γ molecules. Kammert?ns said: "IFN-γ is one of the most important 'weapons' in the T-cell 'armory'."
Optimized T cell therapy
This research provides clues to how scientists can improve T cell therapy for solid tumor treatment. Professor Thomas Blankenstein, the author of the study, explained: "We want to figure out exactly how T cells target tumors. The 'infrastructure' that destroys tumors may be more effective than killing individual cancer cells."
In addition, Kammert?ns said that the importance of this research is not limited to cancer treatment. Interestingly, the mechanism by which IFN-γ eliminates solid tumors is similar to the physiological degradation of blood vessels during development. IFN-γ may affect the formation of new blood vessels after a stroke or heart attack.
1 Cell, 1 NEJM! The importance of IFN-γ has been confirmed many times
Regarding the importance of IFN-γ in cancer immunotherapy, scientists published two key articles in NEJM and Cell magazine last year. Both papers reveal why some patients do not respond well to immunotherapy (PD-1 antibodies, CTLA-4 antibodies).
The study, published in NEJM entitled "Unmasking PD-1 Resistance by Next-Generation Sequencing," uses next-generation sequencing technology to discover that the mechanism behind the PD-1 antibody pembrolizumab resistance is also associated with IFN-γ. The genetic variation detected in the study is related to two signaling pathways. One of the pathway changes resulted in a lack of response to IFN-γ by tumor cells, involving functional deletion mutations in the JAK1 and JAK2 encoding genes. In vitro studies have shown that JAK mutations cause tumor cells to completely lose sensitivity to IFN-γ.
A study published in Cell magazine entitled "Loss of IFN-γ Pathway Genes in Tumor Cells as a Mechanism of Resistance to Anti-CTLA-4 Therapy" also confirmed that melanoma relies on genetic mutations in the IFN-γ pathway to resist CTLA. Treatment of -4 antibodies. James P. Allison, the pioneer of immunotherapy, is the co-author of the study, and his wife, Dr. Padmanee Sharma, is the author of the communication.
James Allison and Padmanee Sharma
Previous studies by Sharma and colleagues have shown that ipilimumab treatment can lead to an increase in IFN-γ produced by T cells. Therefore, the team proposed a hypothesis that defects in the IFN-γ pathway of tumor cells may be resistant to ipilimumab.
By analyzing 16 melanoma patients treated with ipilimumab (4 patients responding to ipilimumab and 12 other patients not responding) to the whole exome gene sequencing data in the tumor, they found that the IFN-γ pathway in non-responsive patients There were an average of 15.33 mutations in the gene. In addition, 9 of the 12 unresponsive patients were detected for copy number changes. The most important changes include the genomic deletion of two IFN-γ receptors (IFNGR1 and IFNGR2) and two important downstream genes (IRF-1 and JAK2). In addition, two known IFN-γ pathway inhibitors (SOCS1 and PIAS4) were "amplified".
The researchers validated this finding using cell and mouse model studies. In melanoma cell lines susceptible to IFN-γ challenge, knocking out IFNGR1 allows tumor cells to continue to grow, even in the presence of IFN-γ. The researchers used the same cell line in a mouse model and treated mice with ipilimumab. It was found that only 4 out of 24 mice with intact IFN-γ receptors developed cancer; Of the 25 mice excluding the IFN-γ receptor, 12 developed cancer.
In addition, all untreated mice eventually died with tumor growth, 80% of mice with intact IFN-γ receptors and received ipilimumab survived, mice knocked out of IFN-γ receptor and treated with ipilimumab About half survived.
summary
At present, in the field of cancer immunotherapy, cracking the mystery of drug resistance and expanding the application range of such therapies are problems that many scientists are actively solving. Xiaobian used to be "25 miles a year!" Immunotherapy "Winning Cancer, Relying on Strength" summarizes some important research results related to the past year. This year, many research groups have also made new discoveries. Two papers published in Science and Nature in March and April confirmed the importance of CD28 and SLAMF7 molecules for cancer immunotherapy. The revealing of more and more key molecular roles is expected to help such revolutionary therapies help more patients.
Source: Bio-Exploration (micro-signal biodiscover)
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