Immunologists from Unige have discovered the still unsuspected antitumor potential of CD4 T lymphocytes. An important step for new kind immunotherapy.
Faced with cancer, immunotherapy – which aims to strengthen the body’s natural defenses – has a remarkable boom. The majority of these treatments are based on CD8 T lymphocytes, “killer cells” capable of eliminating sick cells.
A team from the University of Geneva (UNIGE), however, explored another way: that of T lymphocytes CD4. Long considered as simple auxiliary cells, these lymphocytes saw their therapeutic potential relegated to the background. However, scientists have discovered that these cells also have a strong capacity to destroy cancer cells, while continuing to support other immune cells. Thanks to cell engineering techniques, the team has managed to reprogram them so that they target a tumor marker present in many cancers, both in adults and in children. These results, published in the journal Science Advancesopen the way to a strategy Therapeutic faster and applicable to a wider range of patients.
Traditionally considered as auxiliary cells, CD4 T lymphocytes produce molecules that support the action of other immune cells. They facilitate in particular their functions, their migration or their proliferation in the body.
Recent works carried out by the Camilla Jandus team, assistant professor at the Department of Pathology and Immunology, at the center of research on theinflammation and at the Translational Research Center in oncohematology from the Faculty of medicine From Unige, show that their role has been largely underestimated.
These cells effectively target melanoma, but also lung, ovary, sarcoma and brain cancer, while sparing healthy cells.
In collaboration with the Department of CHUV-Unil oncology and the Lausanne branch of the Ludwig Institute for Cancer Research, Unige scientists have studied the molecular characteristics of T CD4 lymphocytes with people with melanoma (skin cancer). They and they then identified a unique subset bearing a T lymphocytes receptor (called TCR) capable of effectively recognizing a specific antigen for tumor cells: NY-ESO-1. This TCR was then isolated and then artificially expressed in other CD4 T cells.
“We then evaluated the effectiveness of these modified cells against cancer cells, both in vitro and in animal models,” explains Camilla Jandus. “The results are impressive: they effectively target melanoma, but also lung, ovary, sarcoma and brain cancers, while sparing healthy cells. This shows that TCR TC4 cells can directly tackle tumors, in addition to their assistant role.”
The major asset of a widespread allele
The HLA system is a set of genes responsible for immune recognition. Each individual inherits different versions of these genes, the alleles. “They code for cellular surface proteins, HLA molecules, which allow T cells to distinguish healthy cells from cells infected with pathogens or tumor cells”, specifies the researcher.
“The effectiveness of therapies based on T cells thus depends on the presence in the patients of the specific HLA allele, which presents the tumor antigen. However, the NY-ESO-1 antigen, recognized by our TCR, is presented by a allele carried by half of the population of European origin, against only 10 to 15% for other HLA alleles.” This considerably increases the number of patients who could benefit from it, especially since the targeted antigen is expressed in many types of cancers.
Hope for adult and pediatric cancers
The Camilla Jandus team is currently preparing a first clinical trial of cellular cell therapy CD4 and the modified TCR. The objective is to include different types of cancer expressing the NY-ESO-1 antigen. An HLA test will first make it possible to check the presence of the right allele, then the tumors will be analyzed to confirm the expression of the antigen. The CD4 T cells will then be removed, modified in the laboratory to express the TCR, multiplied, then reinjected to the patients.
But Camilla Jandus is considering an additional step: the creation of a bank of immune cells modified with a ready -to -use TCR, from healthy donors, which would save precious time, particularly in the face of aggressive cancers. This strategy could also pave the way for treatment for cancers that are incurable today, especially in children: the first in vitro tests on pediatric neuroblastomas are promising.
