T-Cell “ImmunoMap” Could Increase Response Predictability

Johns Hopkins’ scientists have crafted a digital map, also called “ImmunoMap”, although still undergoing development, that can someday be used to identify which cancer patients will respond successfully to immunotherapies. This digital map addresses the variability of T-cell receptors which are chemical antennas that identify antigens and trigger an immune response.

Through this digital map, researches were already able to pinpoint that cancer patients may respond better to immunotherapy vaccines and treatments when they have a more diverse range of T-cell receptors.

The lead author of the study, Jonathan Schneck, MD, PhD, who is also Johns Hopkins University School of Medicine’ professor of pathology, medicine, and oncology, shared in a press release that ImmunoMap enables researchers to have a clearer picture of the wide variety of the responses of the immune system to cellular antigens. This study entitled “ImmunoMap: A Bioinformatics Tool for T-Cell Repertoire Analysis” can be found in the Cancer Immunology Research journal.

Our immune system’s T-cells feature receptors in their membrane that recollects antigens which are foreign molecules. When a corresponding receptor detects a specific antigen, this event triggers a counterattack which then eradicates the threat.

Cancer cells also have the ability to express antigens and send alerts to the body’s immune system, but they have also developed ways to avoid T-cells detection which allows tumors to cultivate unchecked. To defeat this and eradicate cancer cell, several cancer immunotherapies are applied through a response by the immune system while keeping the healthy cells intact.

An MD and PhD student at Johns Hopkins John-William Sidhom, who was also the study’s first author, said that researchers actually don’t know much as needed about this phenomenon and the T-cells that recognize them despite their knowledge of immunotherapy today which is built in the presumption that they know these antigens. Sidhom produced a mathematical model that serves as a digital map, the ImmunoMap, of the genetic sequence of receptors from human T-cells that were vulnerable to a virus. Sidhom shared that the goal of having this digital map is to group similar T-cell receptors that may target the same antigen.

With this goal in mind, researchers mapped the collection of T-cell receptors and then converted their similarities or differences into a numeric distance with the aid of high-powered computers. To put it simply, if the sequences of two receptors are the same, the computer would assign them a short distance. However, if they have different sequences, they would be assigned to a greater distance. Once all of these are analyzed, the computer will look for patterns among the receptors.

“By characterizing receptor sequences as they relate to each other, we got ImmunoMap. T-cell receptors that are very similar, with slight differences in their sequences, may be recognizing the same antigen,” Schneck said.

To gauge the ImmunoMap’s capabilities, researchers have examined tumors of 34 cancer patients who were being treated with Opdivo (Nivolumab). Three out of the 34 patients with melanoma reacted to the therapy. They had more T-cell receptors compared to the 8 or 9 clusters of the non-responders, with 15 on average. However, upon observance after four weeks of therapy, these responders’ diversity of T-cell receptors decreased by 10 or 15 percent. Schneck explained that the patients had a wide array of receptor weaponry before they underwent treatment which was a factor in allowing the right receptor to kill their cancer cells. Once the right receptor was found by the immune system, the T-cells with those receptors will multiply, which will lead to the overall diminution on the structural diversity of their T-cell receptors.

Contrary to what some scientists believed, these results argue that the T-cells’ ability to infiltrate a tumor is not the only factor to identify patient responses to immunotherapy. Schneck also added that as much as infiltration is important, it is not enough to explain patients’ variable responses to immunotherapy drugs.

As promising as ImmunoMap sounds, scientists say that they need more information to accurately predict which patients will respond to immunotherapies.

Schneck concluded that at this point in time, the ImmunoMap can’t match the T-cell receptors to specific antigens or event determine whether those antigens are vital for immunotherapy response in any cancer patient.