The success of cancer immunotherapy may hinge on T-cell receptor binding and signal strength, according to St. Jude Children’s Research Hospital scientists. They found that how tight a parental T-cell grabs a cancer protein determines if its daughter cells will be anti-cancer effectors or exhausted.
“We found that T-cell receptor binding and signal strength sets up a Goldilocks scenario,” said corresponding author Benjamin Youngblood, PhD, St. Jude department of immunology. “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.”
Their study was published in Nature Immunology, the first author is Xin Lan.
Cancer immunotherapies are some of the most successful drugs in the world. They include Ipilimumab (Yervoy), Pembrolizumab (Keytruda), and Nivolumab (Opdivo). Such drugs made up a world market of $156.8B in 2023, and are expected to rake in $168.1B this year. But only about 15–20% of patients respond to the drugs, and it’s been hard to figure out why.
One of the known keys to a good effect in immunotherapy is generation of a lot of aggressive T-Cells that can attack cancer cells. Immunotherapy’s anti-cancer activity, has shown promise in treating leukemias but has not yet been effective in solid tumors. One reason may be the conversion of potential cancer-killing T cells into an inactive “exhausted” state near the tumor, because of effects of the tumor microenvironment.
Each T cell has a special detection protein on its surface, the T-cell receptor, which binds to a single cancer-related protein, a process that stimulates the immune cell to destroy the cancer. The St. Jude team showed that a “medium” binding strength between the T-cell receptor and the cancer protein results in the best anti-cancer activity in mouse models.
Anti-cancer potential is decided early in a T cell’s life when it engages with other immune cells that alert the T cell of a tumor’s presence. It is now well-appreciated that uncontrolled tumors can indeed be recognized by patients’ T cells but have lost their ability to kill the tumor and subsequently become exhausted from their fight.
Efforts to understand this exhausted state have revealed that the T cell was, in fact, capable of killing the tumor during the initial immune response but had subsequently lost its killing potential. Because these “progenitor” T cells retain tremendous anti-tumor potential, there is great interest in determining how to maintain them and the mechanisms that promote their transition into the non-functional exhausted T cell.
The St. Jude investigators discovered the tightness of the bond between a progenitor T cell and a tumor-surveying immune cell determines the functionality of the progenitor’s offspring. If binding is too tight or loose, the progenitor T cells develop into exhausted cells. Only when the parental cells’ T-cell receptor managed a Goldilocks middle-ground binding strength were cancer-killing effector cells created.
“We need to pay closer attention to T-cell stimulation as they enter the tumor microenvironment,” Youngblood said. “It’s not good enough just to pick any tumor antigen. We must pick a tumor antigen that gives an optimal signal when picking antigens for approaches such as therapeutic vaccination or CAR T cells. We now know to ask: Are they too strong? Are they too weak? Or are they just right?”
