A novel immunotherapy to fight cancer

Cancer immunotherapy consists in manipulating immune cells in patients to fight cancer. The specificity of immunotherapy is to stimulate or boost healthy immune cells in the human body, so these cells can in turn kill the cancer cells that form the tumor. Often indeed, anti-tumor immune defenses are paralyzed by cells or molecules that prevent immune cells from killing cancer cells, allowing the tumor to settle and grow.

In 2004, Sophie Lucas, now president of the de Duve Institute at UCLouvain, decided to tackle the following question: “How are anti-tumor immune responses blocked in cancer patients?”. More precisely, she wanted to understand how a very special type of cells called Regulatory T lymphocytes, or Tregs, exert potent “immunosuppression” within tumors. In 2009, the young UCLouvain researcher discovered GARP, a molecule located on the surface of Tregs.

In 2018, Sophie Lucas finally managed to understand the role of GARP: the molecule acts as a messenger for Tregs, by sending inhibitory signals that block immune defenses. She then developed a tool (anti-GARP antibodies) to neutralize the inhibitory messenger and prevent it from sending its paralyzing signal. This important discovery was published in Science. It allowed the team to propose using anti-GARP antibodies as a new immunotherapeutic agent (a new drug) against cancer.

Septmber 2020. Nature Communications publishes the results of the first tests carried out by Sophie Lucas and her team to evaluate the new drug. Their conclusions are very promising: the scientists succeeded in neutralizing Tregs in tumor-bearing mice using anti-GARP antibodies. When the inhibitory messenger was neutralized, anti-tumor immune responses were no longer paralyzed and started to eliminate cancer cells. The result? Tumors regressed quickly, provided that the anti-GARP antibodies were combined with another immunotherapy (so-called PD1 blockade proven to work in patients. The bet of Sophie Lucas' team? Combine the two complementary immunotherapies, which act on distinct pathways of the immune system, to increase the efficacy of treatments against cancer. And it worked!

What will happen next? Similar tests will be carried out in cancer patients, with the hope to provide a more effective therapy against cancer

The work on GARP has been supported a.o. by WELBIO as part of the project “Functions of intratumoral lymphocytes” led by Pr. Pierre Coulie, co-author of this latest paper. Sophie Lucas is now also a WELBIO investigator with a different project dedicated to auto-immunité.

Source and Illustration : de Duve Institute

References :
de Streel, G., Bertrand, C., Chalon, N., Liénart, S., Bricard, O., Lecomte, S., … Lucas, S. (2020). Selective inhibition of TGF-β1 produced by GARP-expressing Tregs overcomes resistance to PD-1/PD-L1 blockade in cancer. Nature Communications, 11(1), 4545. https://doi.org/10.1038/s41467-020-17811-3