Researchers at The University of Texas MD Anderson Cancer Centre have discovered a new way in which T cells attack acute myeloid leukaemia (AML) cells, which may help explain why AML is particularly sensitive to immune-based treatments and could guide the development of future cancer immunotherapies.

The study, published in Proceedings of the National Academy of Sciences (PNAS), was led by Cassian Yee, M.D., professor of Melanoma Medical Oncology, and Kapil Saxena, M.D., former member of the Yee laboratory.

The findings reveal that leukaemia cells, which lack the molecular machinery normally required for T cell recognition, use a different pathway that depends on the CD64 protein and an intact T cell receptor (TCR).

“By chasing a simple, unexplained observation, we challenged a basic assumption about how T cells can recognise and kill tumour cells,” Yee said.

“The freedom to explore things that aren’t conventional is what drives innovation, and this contrarian finding is an example of that, with broad implications for overcoming immune resistance in leukaemia and possibly other cancers.”

What makes AML difficult to treat?

AML is an aggressive blood cancer that begins in the bone marrow and can progress rapidly.

Although targeted therapies and stem cell transplantation have improved outcomes for some patients, many individuals experience relapses or develop treatment resistance.

One challenge is that cancer cells can evade immune attack by reducing or losing immune signalling molecules, a set of proteins known as the major histocompatibility complex (MHC) which normally helps T cells identify their targets.

What did the researchers discover about the way T cells eliminate AML cells?

T cells typically recognise cancer through their TCR, which binds to specific cancer-related peptides displayed on MHC molecules.

The researchers expected that removing MHC from AML cells would prevent T cell attack.

Instead, activated T cells were somehow still able to efficiently eliminate the AML cells.

This pattern was seen in multiple AML cell lines and in primary samples from patients with AML, including those with high-risk mutations and relapsed disease.

Why was this new pathway surprising?

The researchers suspected that this mechanism might be driven by pathways associated with natural killer (NK) cells, which are not dependent on MHC molecules.

However, disrupting several known NK cell pathways did not eliminate the effect.

Since MHC molecules did not seem to be required, the researchers hypothesised that the TCRs also were unnecessary for this alternative killing pathway.

Surprisingly, the T cells lost their ability to destroy the leukaemia cells when the researchers removed TCRs.

This means that T cells can destroy AML cells through a different, unknown pathway that is MHC-independent but TCR-dependent.

In other words, T cells still require an intact and activated TCR signalling system, but they are not using it in the conventional way scientists have understood for decades.

How did the researchers identify the key drivers in the new pathway?

After testing several known immune pathways, the researchers performed a genome-wide CRISPR screen, repeatedly exposing genetically modified AML cells to T cells to search for genes that allowed the leukaemia cells to survive.

This approach highlighted CD64, a receptor commonly expressed on early myeloid cells, as well as genes involved in interferon-gamma signalling.

Removing CD64 made AML cells resistant to T cells, while adding CD64 into normally resistant AML cells made them more susceptible.

What do these findings mean and what are the next steps?

Overall, these findings revealed a previously unknown mechanism of T cell-mediated killing that depends on CD64 and activated TCR, but not on traditional MHC recognition.

The results suggest that T cells have an additional way to attack leukaemia, which may help explain why AML may be especially sensitive to stem cell transplantation, which is one form of immune-based therapy.

The researchers continue to investigate exactly how CD64 and the TCR signalling machinery interact, with future studies exploring how these mechanisms might be leveraged to improve T cell therapies for AML and possibly other cancer types.

Source: University of Texas M. D. Anderson Cancer Center