Study reveals new obstacle to development of immunotherapies

This is why an unexpected discovery by researchers at the University of Notre Dame and their collaborators, related to how two different peptide antigens react with a T-cell receptor (TCR), launches a new process of building better molecules to develop immunotherapies.

The surprising research showing the adaptability of peptides was published Monday, September 17 in Nature Chemical Biology. Brian Baker, John A. Zahm, CSC, Professor of Structural Biology and Chair of the Department of Chemistry and Biochemistry, was principal investigator of the study and worked with co-authors of Notre Dame, L & # 39; Stanford University, Loyola University and the University of Kentucky.

"Essentially, we've discovered that T cell receptors can be much more responsive than we had previously envisioned, which is somewhat worrisome for the entire field," said lead author Timothy Riley, a former assistant Baker's research. Scientific leader of the Structured Immunity start-up, a company incubated through the IDEA Center of Notre Dame, which aims to reduce the risks related to immunotherapy at an early stage.

T cells are a subtype of white blood cell responsible for detecting whether you are in good health or if you have an infection, but they often ignore cancer cells as a potential threat. In T cell immunotherapy, some of the cells are engineered to contain receptors that allow T cells to search for and destroy specific, unwanted cells when the receptor reacts with specific peptide antigens, an action necessary to induce a response. immune. Although the treatment is effective in some cases, in others, it can destroy healthy cells. As a result, researchers seek to predict reactivity and ensure that the reaction only affects the cells they wish to target.

Scientists knew that there were several million other peptides, or antigen targets, than TCRs. They expected the receptors to be recognized and adjusted to many peptides with similar properties. In the case of the TCR studied in the current research, DMF5, the researchers knew to recognize hydrophobic peptide antigens, which are insoluble in water. But K. Christopher Garcia, a younger family professor and professor of structural biology at Stanford University, alerted Baker of an anomaly discovered in his own research. Garcia noticed that DMF5 also seemed to bind to a different class of peptides – a highly charged and easily soluble compound.

Baker's laboratory, which has experience in analyzing this TCR, has decided to deepen it.

"We thought the TCR was a little unaware of the small differences (in the very busy target) and we simply found similar things to recognize," said Baker, who is also affiliated with the Institute for Cancer Research. Harper. "But it was wrong, we discovered that this peptide has moved and adapted so that the receptor binds in a way that no one had seen before. "

The two different peptide antigens functioned as well on binding with DMF5, stimulating the receptor and inducing an immune response. "It does not matter how it works, as long as the link happens," said Riley.

Although the discovery is remarkable for increasing understanding of how to develop immunotherapies, it is an unexpected challenge to overcome, Baker explained. Although the current research was conducted on a single TCR and only two peptides were evaluated, it is likely that others work similarly.

"What's important is that people are trying to make predictions to develop these models of therapy, and the types of ways to recognize targets," he said. "And it's a new, unexpected complication."

The researchers realized that some RCTs can attack healthy cells, as well as those that threaten their lives, and have incorporated this concern into their studies. "But for those who are trying to take advantage of this biology to develop immunotherapies, you need to worry about this new problem and incorporate it into the design platform that you have," Baker said.

Armed with this new discovery, however, Riley is up for the challenge. "Now that we have excellent examples of T cell receptors recognizing several peptide antigens that are structurally different, we can use them to build hypotheses and test predictions," he said.

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More information:
Timothy P. Riley et al., Cross-reactivity of T-cell receptors increased by the dramatic adaptability of peptides and MHC, Nature Chemical Biology (2018). DOI: 10.1038 / s41589-018-0130-4