A good/bad turn: breast cancer hijacks developing-killer cells to acquire cancer promoting features

Regulatory T cells (Treg) are a type of immune cells that protect tissues from dysregulated immune attack. Unfortunately, these cells also inhibit tumor destruction and release molecules that promote cancer, representing a major barrier to anti-cancer immunity. Treg cells are found in higher numbers within tumors and correlate with decreased life expectancy. How these cells accumulate in human tumors has been unclear so far. RCI scientists found out that breast cancer can hijack killer precursors turning them into Treg cells that can favor tumor growth. The findings are the result of a collaboration between RCI, the Wellcome Sanger Institute and the NCT/DKFZ. The study is now published in the journal Nature Communications.

Our immune system is armed with T cells that can distinguish both foreign and cancer molecules, from our own healthy tissues through the T-cell receptor (TCR). Each T cell is equipped with a unique TCR-‘fingerprint’, which recognizes and binds particular cancer molecules, resulting in T-cell activation. While killer T cells recognize and destroy tumors, Treg cells inhibit killer T cell function to protect healthy tissues from damage, but they also hinder tumor eradication.

Using laser beams Maria Xydia, Ph.D., isolated individual T cells from tumors and blood of breast cancer patients and sequenced the genetic material of each cell separately to identify its TCR-fingerprint. She discovered that Treg cells infiltrating the tumors do not share common fingerprints with those circulating in the blood. “We were surprised by these results since until now scientists believed that Treg cells accumulated in tumors through migration from the blood and proliferation within the tumor microenvironment” said Maria Xydia. Unexpectedly, killer T cells and Treg cells infiltrating the tumors shared many fingerprints, revealing that they were born from the same T cell. When Xydia looked deeper into the genes expressed in each cell, she could identify their common ancestors in the tumor among activated T cells, which had only recently met their antigen but not yet developed any killer or Treg characteristics.  “Having identified a common progenitor signature between immune suppressive Treg and killer cells isadiscovery of fundamental importance because it will enable us to identify the factors that can tip the balance towards a beneficial killer T cell fate to eradicate tumors” noted Prof. Philipp Beckhove, the senior author of the study.

The researchers plan to investigate which molecules promote the common precursors to develop into tumor-promoting Treg cells rather than killer cells. “Bioinformatic analysis predicts that more than a thousand genes are possibly involved in this decision. Such factors can be targeted by drugs, antibodies or genetically-engineered killer T cells to augment the efficacy of cancer immunotherapy.”, noted Xydia. Lastly, they would like to extend their analyses on different tumor types to determine if turning killer precursors into suppressive Treg cells is relevant also to cancer types other than breast cancer.

For more information, please visit the full article in the journal Nature Communications:

Xydia M., Rahbari R., Ruggiero E., Macaulay I., Tarabichi M., Lohmayer R., Wilkening S., Michels T., Brown D., Vanuytven S., Mastitskaya S., Laidlaw S., Grabe N., Pritsch M., Fronza R., Hexel K., Schmitt S., Müller-Steinhardt M., Halama N., Domschke C., Schmidt M., von Kalle C., Schütz F., Voet T. and Beckhove P. Common clonal origin of conventional T cells and induced regulatory T cells in breast cancer patients. Nat Commun12, 1119 (2021). https://doi.org/10.1038/s41467-021-21297-y