The immunotherapy – a drug treatment that stimulates the immune system to attack tumors – works well against some types of cancer, but has had mixed success against lung cancer.
In a mouse study, researchers discovered that bacteria naturally found in the lungs help create an environment that suppresses T-cell activation in lymph nodes near the lungs.
The researchers did not find that kind of immunosuppressive environment in the lymph nodes near the tumors growing close to the skin of the mice. They hope that their findings may help develop new ways to stimulate the immune response against lung tumors.
Maria Zagorulya, a graduate student at MIT, is the lead author of the paper, published in the journal Immunity.
“There is a functional difference between the responses of T cells that mount in different lymph nodes. We hope to find a way to counteract that suppressive response, so that we can reactivate the T cells that work against lung tumors,” explains Stefani Spranger, lead author of the new study.
Scientists have known for many years that cancer cells can send immunosuppressive signals, leading to a phenomenon known as T-cell depletion. The goal of cancer immunotherapy is to rejuvenate those T-cells so they can attack again. to tumors.
One type of drug commonly used in immunotherapy are checkpoint inhibitors, which slow down depleted T cells and help to reactivate them. This approach has worked well for cancers like melanoma, but not so well for lung cancer.
Spranger’s latest work offers a possible explanation: He has discovered that some T cells stop working even before they reach the tumor, because they are not activated early in their development. In a paper published in 2021, he identified dysfunctional T cell populations that can be distinguished from normal T cells by a pattern of gene expression that prevents them from attacking cancer cells when they enter a tumor.
“Even though these T cells proliferate and infiltrate the tumor, they never had a license to kill,” Spranger says.
In the new study, his team delved into this failure to activate, which occurs in the lymph nodes, which filter fluids that drain from nearby tissues. Lymph nodes are where “killer T cells” meet dendritic cells, which present antigens (tumor proteins) and help activate the T cells.
To find out why some killer T cells don’t activate correctly, Spranger’s team studied mice with tumors implanted in the lungs or flanks. All tumors were genetically identical.
The researchers found that these T cells also interfere with the ability of dendritic cells to activate killer T cells that attack lung tumors.
The researchers found that T cells from lymph nodes draining from lung tumors did find dendritic cells and recognized tumor antigens displayed by those cells. However, these T cells did not become fully activated, due to the inhibition of another population of T cells called regulatory T cells.
The researchers found that these regulatory T cells were strongly activated in lymph nodes draining from the lungs, but not in lymph nodes near the flank tumors. Normally, regulatory T cells are responsible for preventing the immune system from attacking the body’s own cells. However, the researchers discovered that these T cells also interfere with the dendritic cells’ ability to activate the killer T cells that attack lung tumors.
The researchers also discovered how these regulatory T cells suppress dendritic cells: by removing stimulatory proteins from the surface of dendritic cells, preventing them from activating killer T cell activity.
microbial influence
Other studies revealed that regulatory T cell activation is driven by elevated levels of gamma interferon in lymph nodes draining from the lungs. This signaling molecule is produced in response to the presence of commensal bacteria, that is, bacteria that normally live in the lungs without causing infection.
The researchers have not yet identified the types of bacteria that induce this response or the cells that produce interferon gamma, but they did show that when they treated mice with an antibody that blocks interferon gamma, they could restore killer T cell activity.
Gamma interferon has various effects on immune signaling, and blocking it can dampen the overall immune response against a tumor, so using it to stimulate killer T cells would not be a good strategy for patients, Spranger says. His lab is now exploring other ways to stimulate the killer T cell response, such as inhibiting regulatory T cells that suppress the killer T cell response or blocking signals from commensal bacteria, once researchers identify them.