27 April 2020

A new therapeutic strategy for lymphoma could be developed after scientists in Switzerland identified a key mechanism that tumour cells use to avoid detection from the immune system.

A team of researchers at École Polytechnique Fédérale de Lausanne (EPFL) found that in some non‑Hodgkin’s lymphoma (NHL) patients, their cells carry an activating mutation in the protein cathepsin S. This protein is responsible for cutting other proteins into small fragments, which are then presented as antigens on the surface of cells.

Elie Dheilly, one of the study’s lead authors, said: “When cathepsin S is active, cancer cells interact with immune cells called CD4+ T cells, which help the tumour to grow, while they maintain social distance with CD8+ T cells, which would attack and kill the tumour.”

This discovery prompted the researchers to genetically remove cathepsin S from mouse lymphoma cells to understand how tumour growth would be affected. They found that inhibiting cathepsin S reduced tumour growth in mice by inverting the communication with T-cells: CD8+ T cells attacked the tumour, while CD4+ T cells were kept at bay.

The team believe this happens by inducing antigen diversification, which generates a different population of antigens on the surface of the cancer cells, helping T cells to identify and kill the tumour. Their findings were published in the journal Cancer Cell.

Prof Elisa Oricchio, who led the research team, said: “We think that cathepsin S could represent an important therapeutic target.

“Inducing antigen diversification is an attractive therapeutic strategy to increase tumour immunogenicity and enhance response to immunotherapies in lymphoma but possibly also in other tumour types.”

Co-lead author Elena Battistello developed a new imaging technique to specifically measure the activity of cathepsin S. This has since been used by the team to identify and further develop new inhibitors that could be used to improve the treatment of patients diagnosed with NHL.

Source: Dheilly E, Battistello E, Katanayeva N, Sungalee S, Michaux J, Duns G, Wehrle S, Sordet-Dessimoz J, Mina M, Racle J, Farinha P, Coukos G, Gfeller D, Mottok A, Kridel R, Correia BE, Steidl C, Bassani-Sternberg M, Ciriello G, Zoete V, Oricchio E. (2020) “Cathepsin S regulates antigen processing and T cell activity in Non-Hodgkin Lymphoma”, Cancer Cell, doi: 10.1016/j.ccell.2020.03.016


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