When you need a little motivation, it often has to come from within. New research suggests that cancer-fighting immune cells have found a way to do just that.
Scientists at the University of California, San Diego have discovered a property of T cells that could inspire new antitumor therapies. Through a previously undescribed form of cellular self-signaling, T cells were shown to become activated in peripheral tissues, fueling their ability to attack tumors.
The study, published on May 8, 2023 in Immunitywas led by the study’s first author and postdoctoral fellow Yunlong Zhao, PhD, and co-senior authors Enfu Hui, PhD, professor, UC San Diego School of Biological Sciences, and Jack D. Bui, MD, PhD, professor of pathology at University of California San Diego School of Medicine.
T cells are a type of white blood cell that protects against infection and helps fight cancer. In the lymphatic organs, T cells are trained by antigen presenting cells which, as the name suggests, present an antigen (a piece of tumor or pathogen) to the T cells, stimulating an immune response.
A key part of this process is the binding of B7, a protein on the surface of antigen-presenting cells, to CD28, a receptor on T cells. This B7:CD28 interaction is an important driver of the cell’s immune response. T. Once trained, T cells leave the lymphatic organs and travel through the body to find and attack their targets.
Since then, more recent work has revealed that T cells can either make their own B7 or take the B7 protein from antigen-presenting cells and carry it with them, but exactly why they do this isn’t clear. This also led the researchers to wonder if the T cells, now equipped with a receptor and its ligand, could activate on their own.
Through a series of experiments, the researchers discovered that T cells could self-activate by ruffling their cell membrane inward to allow the B7 protein and the CD28 receptor to bind to each other.
“People often assume that the cell membrane is flat, but actually it looks more like a coastline with many coves and bays,” Hui said. “We found that local membrane curvatures are actually a rich dimension of T cell self-signaling, which is a paradigm shift in a field that previously assumed this only occurred between cells.”
The researchers then confirmed that this self-stimulation was indeed effective in boosting T-cell function and slowing tumor growth in a mouse model of cancer.
“When a T cell leaves a lymphatic organ and enters the environment of a tumor, it’s like leaving home and going for a long walk in the woods,” Bui said. “In the same way that a hiker brings snacks to sustain him during the journey, T cells bring their own signal to keep going. Now the exciting question is, how much further will they go if we can provide them with more food?”
T-cell refueling could be achieved by providing more sources of B7 in lymphatic organs or in the tumor itself. Another option, the authors say, would be to develop a cell therapy in which engineered T cells with enhanced self-signaling capabilities are administered directly to a patient.
The researchers also suggest that this system could be used as a biomarker of cancer, in the sense that patients whose tumors contain many B7 T cells are better able to fight the disease.
On the other hand, in patients with autoimmune diseases such as lupus or multiple sclerosis, doctors might prescribe endocytosis inhibitors to prevent the cell from forming concavities, effectively blocking the B7:CD28 interaction to reduce overactive T-cell function.
“We have found a way that T cells can live outside their normal homes and survive in the foreign environment of a tumor, and we can now develop clinical strategies to increase or decrease these pathways to treat disease,” Hui said.
Coauthors include: Yunlong Zhao, Christine Caron, Ya-Yuan Chan, Calvin K. Lee, Xiaozheng Xu, Jibin Zhang, and Takeya Masubuchi at UC San Diego, as well as Chuan Wu at the National Cancer Institute.
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