Triad of Immune Cells Boosts Cancer Immunotherapy Success

One annoying aspect of modern cancer immunotherapy is this. While they can occasionally totally eradicate cancer or significantly reduce it in specific patients, other times they have no effect at all. It’s a puzzle.

Numerous theories have been proposed by scientists to account for the discrepancy. Maybe it has to do with how many mutations a tumor has, where more mutations equal stronger responses. Alternatively, it could be the surrounding tissue environment, where certain conditions promote and others inhibit efficient immune responses. However, none of these justifications have shown to be conclusive or universally applicable thus far.

As of late, researchers from Houston, Texas’s Memorial Sloan Kettering Cancer Center (MSK) and Baylor College of Medicine believe they have a more compelling theory for cancer immunotherapy.

“It turns out that in order for immune cells to effectively kill the cells of a tumor, they need to take on a specific spatial configuration. They need to form a triad.”- Andrea Schietinger, PhD, a tumor immunologist and member of the Immunology Program in MSK’s Sloan Kettering Institute

Triad is short for three cells. However, any three cells will not enough. She goes on to say that what you actually need is for three distinct immune cells to work together simultaneously and in the same location: one helper T cell, one cytotoxic (“killer”) T cell, and one dendritic cell.

From an immunological perspective, these cells are neither uncommon nor rare. These are the typical actors that are mentioned in every textbook on immunology. However, it was unknown until recently that for these cells to effectively mount an immunological defense against cancer cells, they had to be physically present in the same tumors.

Published in the journal Cancer Cell on July 8, 2024, the discovery has urgent therapeutic implications and may change the way physicians deliver cancer immunotherapy.

Looking for signs as to why a superior military force falters

The first author of the new article is Gabriel Espinosa-Carrasco, PhD, a postdoctoral fellow in the Schietinger group. Drs. Schietinger and Espinosa-Carrasco became interested in this field of study because of the copious, often depressing, data from human clinical studies including adoptive T cell treatments. These are treatments in which a patient’s sample of cytotoxic T cells is taken, and those that recognize the malignancy are isolated and multiplied to billions of copies in the lab before being given back to the patient.

“How is this possible that we can generate the most perfect cytotoxic T cells in the lab, give patients billions of these cells, and yet they still fail to eliminate the cancer?” Dr. Schietinger asks. “There seems to be something so fundamental that we are missing about what cytotoxic T cells need to kill effectively.” In retrospect, she says, the answer seems obvious.

Granting T cells a License to Kill
For an extended period, researchers have understood that cytotoxic T cells are not autonomous. For them to become activated and armed, helper T cells are required. This is textbook stuff, as Dr. Schietinger notes.

She notes that this is the reason that crucial molecules produced by helper T cells are added to every current protocol where cytotoxic T cells are activated and ready for adoptive T cell treatment. The idea is that by the time the cytotoxic T cells are reinfused into the body, they should be prepared to combat cancer.

However, what if helper T cells are required by cytotoxic T cells not only in the early stages of becoming armed and activated, but also in order to complete their kill mission? Do cytotoxic T cells require a license to kill, like to that of James Bond? It puzzled Dr. Schietinger.

In order to find out, she and her colleagues created a cancer model in mice that she could treat using an adoptive T cell therapy technique that is presently being utilized on humans. She created two disparate scenarios. She administered solely cytotoxic T cells to the cancer-ridden mice in one instance. On the other hand, she administered helper T cells in addition to cytotoxic T cells to the mice. The outcomes were striking and evident: the mice that had gotten both types of T cells saw their tumors regress.

“What this implies is that just having the cytotoxic machinery up and running is not really enough to do the actual killing,” Dr. Schietinger says. “You need to actually license them to kill the target cell.”

When scientists examined the tumor tissues from the animals under a microscope, it became more evident how that licensing would take place. At that point, they noticed that the cells in the mice that had responded to the medication had assembled into the characteristic immune cell triads. There was a physical nesting of the cells. Dr. Schietinger claims that cytotoxic T cells are finally able to get the word that it is time to act due to the spatial arrangement.

It was a fascinating and thrilling discovery. Would it hold true for any mouse model other than the one they used?

Immune cell triads’ implications for medicine
What effects does all of this have? Initially, these triads may be utilized as a biomarker to determine which people are most likely to benefit from cancer immunotherapy, according to Dr. Schietinger. Currently, physicians lack reliable biomarkers to differentiate between the two.

Secondly, the findings suggest that physicians ought to reconsider the way in which they employ adoptive T cell therapy. Perhaps helper T cells should be given in addition to the majority of killer T cells; perhaps a far smaller number of killer T cells would be sufficient if helper T cells were included as well.

Finally, the findings have implications for the development of cancer vaccines, in which patients’ killer T cells are stimulated by bits of cancer-associated protein.

The goal of Dr. Schietinger’s team is to progress research in each of these areas. A bioengineer on her team, for instance, is creating instruments to link one killer T cell to one helper T cell in order to promote the development of a triad with a dendritic cell, which is the cell type that presents T cells with pieces of cancer proteins.

In order to forward this research into clinical trials, they are also collaborating with other industry leaders and testing novel cancer vaccine formulations.

“The main implication of our findings is that it’s not the absolute numbers of cells that matters, it’s their spatial configuration,” explains Dr. Schietinger. “The three cell types need to be on the battlefield together, and building therapeutics which do that is our next big goal.”

For more information: Intratumoral immune triads are required for immunotherapy-mediated elimination of solid tumors, Cancer Cell, https://doi.org/10.1016/j.ccell.2024.05.025