Cancer immunotherapy works by improving the patient's own immune system so that the body itself can fight cancer cells. This has brought great hope to some types of cancers that were previously difficult to treat. However, the fact that immunotherapy does not work for everyone cannot be neglected, and the reasons are not clear yet. Most researches and new therapies in this field are concentrated on CD8+ T cells. As a type of immune cell, CD8+ T cells recognize and destroy other cells that display cancer antigens. While in contrast, attention has rarely been paid to another type of immune cell, CD4+ T cells, as well as the molecular signals they recognize.
In a new study, researchers from the University of California, San Diego School of Medicine used bioinformatics methods to discover the binding partner of CD4+ T cells, a molecule called MHC-II, whose effect on neonatal tumors may be greater than MHC-I, a well-known binding partner for CD8+ T cells. This finding may help people improve cancer immunotherapy and predict which patients will respond better. The results of the study were published online in the September issue of the Cell Journal, under the heading "Evolutionary Pressure against MHC Class II Binding Cancer Mutations."
The author of the paper, Dr. Hannah Carter, assistant professor of medical science at the University of California, San Diego, said, "The more we understand the ability of a person's immune system to clear them before cancer cells stand firm, the more we can relate this to them. By combining genetic risk factors or environmental exposure information, we may be better able to predict a person's cancer susceptibility."
Some facts about MHC
The study by Carter and her colleague focused on major histocompatibility complexes (MHCs). MHC is a family of molecules displayed on the surface of most cells in the body and can be divided into three broad categories: MHC-I, MHC-II, and MHC-III. MHC obtains almost all antigenic fragments from inside the cell and presents them to T cells so that T cells can constantly examine infected or damaged cells. If T cells find MHC molecules that carry "self" antigens, they will not interfere. But if they find foreign antigens, such as antigens from bacteria or viruses, or self-antigens that mutate, they will kill infected or damaged cells before the damage spreads.
In a previous study published in the Cell Journal (Cell, 30 November 2017, doi:10.1016/j.cell.2017.09.050), Carter, Marty and his team discovered a human MHC-I gene composition and there is a clear correlation between genes that are mutated in this person's cancer. Carter said that this makes sense because the cancer antigens presented by MHC-I cause T cells to eliminate these cancer cells earlier. From the opposite point of view, if a person's MHC-I molecule does not recognize and display cancer antigens, then this particular abnormality is more likely to occur in this person's tumor. This is also clinically meaningful as these researchers found that the fewer cancer antigens a person's MHC-I can recognize, the more likely they may develop cancer.
However, MHC-I does not fully reflect the ability of the human immune system to respond to tumors. Humans also have a related molecule called MHC-II. MHC class I is displayed on the surface of each cell, so any cell can become cancer cells. But MHC-II is only displayed by professional immune cells such as macrophages. MHC-II is also a more complex molecule and is capable of binding a wider range of antigens than MHC-I. These two molecules play an important role in controlling potential tumors: the precursor cells of cancer cells may be able to evade detection of one molecule, but they are unlikely to evade detection of these two.
New discovery about MHC peptide
Being curious about the unfamiliar members of the MHC family, the Carter team focused on MHC-II in this new study. Similar to their MHC-I study, they applied computational biology to data from the Cancer Genome Atlas (TCGA), which is a database established by the National Institutes of Health from genomic information from different human tumors of thousands of species. They scored MHC-II molecules in 5942 patient tumors for their ability to present 1018 cancer antigens in order to assess their CD4+ T cells.
These researchers found that an antigen that is well recognized by a human MHC-II is less likely to appear in his or her tumor than a mutation that is ignored by MHC-II. MHC-II reflects this more than MHC-I. However, the Carter team was surprised to find that unlike MHC-I, the ability of MHC-II to recognize antigen was independent of the age at which a person was diagnosed with cancer.
Carten said, "Imagine that 100 mutant antigens can cause cancer. If a person's MHC-I can only present 20 such antigens, then their coverage will be lower than those who can present 80 antigens. When there are not many mutations, they tend to develop cancer at an earlier age. This is true for MHC-I, but for MHC-II, we failed to find the same correlation, at least not found in this early analysis."
Looking to the future
Carter said that MHC-II is more complex than MHC-I, and the tools to date to study MHC-II are not complicated enough. But as the field continues to progress, she hopes to see scientists and clinicians take into account MHC-I and MHC-II data when developing personalized cancer immunotherapy. She believes that this information may help determine why some people respond to immunotherapy while others do not. More importantly, she hopes that doctors will one day be able to use MHC-I and -II data to predict the response of these patients before they receive immunotherapy, so that patients who do not respond will not suffer from potential side effects due to ineffective treatment.
Dr. Maurizio Zanetti, co-author of the paper and professor of medicine at the University of California, San Diego,
said, "Incorporating MHC into the global context of cancer through genomic analysis is a powerful new way to integrate major immunomodulators to help better understand cancer evolution and its dynamic interaction with the immune system. This may represent a step in our ability to select the best immunotherapy for individual patients, and this will also help to better predict the response to immunotherapy. I think this research is an important step in linking cancer genomics and cancer immunology."
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