Photo: ©2021 EPFL Hatice Altug

Unige.ch

The treatments used to fight against tumors are mainly based on CD8 T lymphocytes, specialized in the detection and elimination of intracellular infections and cancer cell killers. However, some patients do not respond to these treatments. This is why a research team from the Swiss Cancer Center Léman (SCCL), bringing together the universities of Geneva (UNIGE) and Lausanne (UNIL), the Ludwig Institute for Cancer Research (LICR), EPFL, and the CHUV, was interested in CD4 T lymphocytes, which play a supporting role with CD8 T cells, without being able to directly eliminate tumors. Using new nanotechnologies, scientists have found that when linked directly to cancer cells, up to a third of these CD4 T cells can also kill them. This discovery, to be read inScience Advances, is significant and extends the therapeutic perspectives based on CD4 T lymphocytes that could be administered to patients resistant to conventional therapies.

When cancer cells proliferate in our body, our immune system kicks in. The first lines of fighters, capable of killing tumor cells, are CD8 T lymphocytes. They are supported by CD4 T lymphocytes, which secrete factors that they use in this fight. "This is why many cancer treatments are based on CD8 T lymphocytes," explains Camilla Jandus, last author of the study and professor at the Department of Pathology and Immunology of the Faculty of Medicine at UNIGE and assistant scientist at the LICR. Unfortunately, some patients do not respond to these treatments, so we need to find new ones. ”

The SCCL team then focused on CD4 T lymphocytes, precious auxiliaries of our immune system. "These have a much wider spectrum of functional specializations than CD8 T lymphocytes and, for a long time, we were not sure that they had the capacity to transform into killer lymphocytes", specifies Pedro Romero, professor in the Department. of fundamental oncology from the Faculty of Medicine and Biology of UNIL.

20,000 Individual Boxing Rings 

To shed some light on this question, the scientists looked at around twenty patients with melanoma treated at the CHUV. “Melanoma is not the most common skin cancer, but it is the most deadly and is especially sensitive to immunotherapies,” explains Camilla Jandus. They then isolated CD4 T lymphocytes from the blood and fragments of these tumors, with the idea of ​​confronting them directly with the tumor cells taken and observing their behavior individually. Observation tools were then needed for the benefit of very advanced resolution up to the level of the single cell. “We created chips of over 20,000 65 picoliter mini-wells (1 picoliter = 10-12 liter), in each of which we deposited a CD4 T cell and a tumor cell,” explains Hatice Altug, Professor at the EPFL Bionanophotonic System Laboratory. For 24 hours, the researchers photographed these wells every five minutes to observe the interactions that occur between the two cells. "We know that it takes about 2 and a half hours for a CD8 to kill a tumor cell, we chose to observe these boxing rings for 24 hours, not knowing how, and if, the CD4 would react, She continues.

A Third of CD4 are the Winners

To the scientists' satisfaction, the high-throughput integration of dynamic image data reveals that up to a third of CD4 T lymphocytes manage to kill the tumor cell to which they were closely linked within 5 hours. "These direct observations at the level of individual lymphocytes, revealed for the first time at such a level of sensitivity, confirm the existence of CD4 T lymphocytes capable of killing tumor cells, and this while tumor cells sometimes manage to divert them from their function of protective support in order to make them allies, ”emphasizes Pedro Romero.

By analyzing the killer variety CD4 T lymphocytes in detail, they found that they expressed the SLAMF7 molecule, which they used as a weapon. "This is why we are now going to isolate and cultivate in vitro the best CD4 T lymphocytes, the killer variety, in order to make a veritable army of trillions of cells, which we can then inject into the patients in whom the treatments. based on CD8s do not work, ”continues Camilla Jandus. Indeed, naturally, the human body has only a small number of CD4 T lymphocytes directed against tumors, not enough to overcome them. “Thanks to the ability to visualize these close fights with our chip, we have paved the way for expanding the arsenal in the fight against cancer, which we now need to develop,” concludes Hatice Altug.