Immunotherapy – drug therapy that stimulates the immune system to attack tumors – has a good effect on some types of cancer, but its effect on lung cancer is mixed.
A new study helps to clarify why the immune system responds so weakly to lung cancer, even after treatment with immunotherapy drugs. In this study on mice, researchers from the Massachusetts Institute of Technology found that bacteria found naturally in the lungs can help build an environment that inhibits the activation of T cells in lymph nodes near the lungs. They did not find that immunosuppressive environment in the lymph nodes near the tumor growing near the skin of mice. They hope that their findings may help to develop new methods to improve the immune response to lung tumors.
Stefani Spranger, the corresponding author of the paper and member of the Koch Comprehensive Cancer Research Institute of Massachusetts Institute of Technology, said, “There are functional differences between T cell responses initiated in different lymph nodes. We hope to find a way to offset this inhibitory response, so that we can reactivate T cells targeting lung tumors.”
Can’t attack
For many years, scientists have known that cancer cells can send out immunosuppressive signals, which leads to a phenomenon called T-cell failure. The goal of cancer immunotherapy is to reactivate these T cells so that they can start attacking the tumor again.
A drug commonly used in immunotherapy involves immune checkpoint inhibitors, which can remove the inhibition of cancer cells on T cells with failure and help them reactivate. This method has a good therapeutic effect on melanoma and other cancers, but it has a poor therapeutic effect on lung cancer.
Spranger’s recent research has provided a possible explanation for this: she found that some T cells stopped functioning even before reaching the tumor, because they failed to be activated at the early stage of development. In a paper in 2021, she identified the dysfunctional T-cell population. These dysfunctional T cells can be distinguished from normal T cells by a gene expression pattern that makes them unable to attack cancer cells after entering the tumor.
Spranger said, “Although these T cells can proliferate and penetrate into tumors, they are never allowed to kill cancer cells.”
In this new study, her team further studied the activation failure in lymph nodes, which filter the fluid discharged from nearby tissues. Lymph nodes are the places where “killer T cells” meet dendritic cells, which present antigens (tumor proteins) and help activate these T cells.
In order to explore why some killer T cells cannot be activated correctly, Spranger’s team studied mice with tumors implanted in the lung or lateral abdomen. All tumors are genetically identical.
These authors found that T cells in lymph nodes discharged from lung tumors did meet dendritic cells and recognize tumor antigens presented by these cells. However, these T cells were not fully activated, which was due to the inhibition of another T cell population called regulatory T cells.
They found that these regulatory T cells were strongly activated in the lymph nodes discharged from the lung, but not in the lymph nodes near the tumor located in the lateral abdomen. Regulatory T cells are usually responsible for ensuring that the immune system does not attack the body’s own cells. However, they found that regulatory T cells also interfere with the ability of dendritic cells to activate killer T cells targeting lung tumors. They also discovered how these regulatory T cells inhibit dendritic cells: by removing stimulating proteins from the surface of dendritic cells, they prevent them from activating killer T cells.
Effects of microorganisms
Further research shows that the activation of regulatory T cells is at a high level in lymph nodes discharged from the lungs Interferon γ driven. This signal molecule is generated in response to the presence of symbiotic bacteria, which usually live in the lungs and do not cause infection.
These authors have not yet determined the type of bacteria that induce this reaction or produce interferon γ, but they found that when the mice were treated with a kind of antibody to block interferon γ, they could restore the activity of killer T cells.
Spranger said, Interferon γ has a variety of effects on immune signals. Blocking it can inhibit the overall immune response against tumors. Therefore, using it to stimulate killer T cells will not be a good strategy for patients. Her laboratory is now exploring other methods to help stimulate the killer T cell response, such as inhibiting the regulatory T cells that inhibit the killer T cell response or blocking the signals sent by symbiotic bacteria once they are identified.
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Reference
Maria Zagorulya et al. Tissue-specific abundance of interferon-gamma drives regulatory T cells to restrain DC1-mediated priming of cytotoxic T cells against lung cancer. Immunity, 2023, doi:10.1016/j.immuni.2023.01.010.