The research revealed that the strength of a parent T cell’s connection to a cancer-related protein determines if its offspring will function as anti-cancer cells or become ‘exhausted’ T cells. Immunotherapy, which aims to boost the immune system’s ability to fight cancer, has been effective in treating leukemias but has not been as successful with solid tumors. One of the reasons for this limited success is the transformation of potentially cancer-fighting T cells into inactive “exhausted” cells near the tumor. Scientists at St. Jude Children’s Research Hospital discovered that the way a parental T cell binds to a cancer-related protein plays a crucial role in this process.A new study has found that a specific type of T cell, known as a parental T cell, plays a key role in determining whether its daughter cells will become effective in fighting cancer or become exhausted. The research, which has important implications for improving immunotherapy, was recently published in the scientific journal Nature Immunology.
T cells are a crucial part of the body’s immune system and are responsible for identifying and destroying cancerous cells. Each T cell contains a unique detection protein on its surface, called the T-cell receptor, which attaches to a single cancer-related protein. This binding process activates the T cell and triggers it to attack the cancer cells. The study conducted by the St. Jude research team revealed that the strength of the bond between the T-cell receptor and the cancer protein plays a significant role in determining how the T cell will respond to the cancer.proteins, resulting in the most effective anti-cancer activity in mice models.
The study, led by corresponding author Benjamin Youngblood, PhD, of the St. Jude Department of Immunology, found that the binding and strength of T-cell receptors sets up a balance that is crucial for anti-cancer activity. “We found that T-cell receptor binding and signal strength sets up a Goldilocks scenario,” said Youngblood. “Too much stimulation will drive the T cells to a terminal state, limiting their ability to fight cancer. But too little stimulation may also cause them to become dysfunctional. You want to hit that ’just right’ state.”
Early T-cell activation determines anti-cancer potential
The potential for anti-cancer activity is determined early in a T cell’s life when it interacts with other components of the immune system -functional T cell that is exhausted. The researchers at St. Jude found that the strength of the bond between a progenitor T cell and an immune cell that surveys tumors determines the functionality of the progenitor’s offspring. If the binding is too tight or too loose, the progenitor T cells turn into exhausted cells. Only when the T-cell receptor of the parent cell managed to have a middle-ground binding strength were cancer-killing effector cells created. “It really is a beautiful and simple mechanism,” said Youngblood. “Optimal stimulation enables sustained contact with a cell that can provide healthy or good.”The researchers discovered that when T cells are stimulated too much, they become exhausted and lose their ability to detect cancer signals. On the other hand, when T cells receive low stimulation, they are unable to stay in contact with the cells presenting cancer proteins, causing them to enter a more suppressive and toxic state.”
Furthermore, the authors found that optimal interaction occurs between T cells and dendritic cells, which are a different type of white blood cell. Dendritic cells play a crucial role in monitoring cancer. After coming into contact with the tumor, dendritic cells present fragments of cancer-related proteins to T cells. When the T-cell receptor binds to the presented cancer protein within the ideal strength range, the researchers observed an increase in T-cell activity.Cell growth and activation in laboratory settings and living organisms. If the connection between cells was not strong enough, the original cell would move away from the dendritic cell and encounter its own malfunction. The researchers pinpointed the specific genes and epigenetic changes linked to each result, offering valuable information to enhance future T-cell treatments.
Enhancing T-cell therapies for combating cancer
Present immunotherapies heavily depend on T cells. One category of these therapies, known as immune checkpoint inhibitors or blockade, stop the tumor from deactivating T cells. However, this approach has demonstrated limited effectiveness when the pool of progenitor cells is lacking.
Youngblood’s research has shown that only fully exhausted T cells remain after the depletion of other T cells. This discovery could lead to improvements in novel therapies and the timing of their administration, ultimately increasing efficacy.
According to Youngblood, the population of progenitor T cells, rather than exhausted T cells, is the one that responds to checkpoint blockade. Without this population, there is no therapeutic response to checkpoint blockade. Understanding the transition from progenitor to the dysfunctional exhausted state is crucial for advancing T cell-based immunotherapies in solid tumors.The research focused on the tumor microenvironment.” In addition to checkpoint inhibitors, the findings could potentially enhance immunotherapy by altering a patient’s immune cells with an artificial T-cell receptor. This artificial chimeric antigen receptor (CAR) is designed to target a specific cancer-related protein (antigen), which triggers T-cells to attack the tumor. The results suggest that the selection of CAR targets could be refined. “We need to pay closer attention to T-cell stimulation as they enter the tumor microenvironment,” said Youngblood. “It’s not sufficient to simply choose any tumor antigen. We must select a tumor antigen that provides an optimal signal.”The use of therapeutic vaccination and CAR T cells prompts the question: Are they too powerful? Are they too weak? Or are they just right?”
