GARP in cancer: the story continues…

Sophie Lucas (WEL Research Institute – UCLouvain) and her team identified GARP as a novel immuno-oncology target in 2009 which led, a decade later, to the initiation of a clinical trial, currently underway, in solid tumors with an industrial partner.  Here, the team showed that this GARP blockade strategy also has a therapeutic potential in “liquid” tumors such as myeloproliferative neoplasms.

This result is part of a long series of research carried out by the Institut de Duve team:

• 2004: Project initiation to understand the functioning of regulatory T-lymphocytes (Tregs) which block immune responses in the event of cancer.
• 2009: Discovery of the GARP molecule on the surface of Tregs. 
• 2018: Understanding the role of GARP: the molecule acts as a messenger for Tregs, sending signals that sabotage immune responses against tumours. Sophie Lucas then succeeded in developing anti-GARP antibodies able to neutralize the blocking effect of GARP on the immune system. This important discovery was published in Science.
• 2020: The lab showed that anti-GARP antibodies in mouse induced regressions of mouse tumors otherwise resistant to anti-PD-1 immunotherapy. These results were published in Nature Communications and marked the launch of a phase I clinical trial, currently underway, with an industrial partner.

Here, Sophie Lucas' group, in close collaboration with the groups of Pierre Coulie and Stefan Constantinescu, both also researchers at the WEL Research Institute at UCLouvain/Institut de Duve, demonstrated that the anti-GARP antibodies developed in the laboratory were also effective against some blood cancers as a monotherapy.  

The group had known for long that GARP, the molecule targeted with the antibodies, was expressed not only on immunosuppressive Tregs, but also on platelets and megakaryocytes, which are abnormally abundant in certain blood cancers such as myeloproliferative neoplasms.  « We studied these blood cancers in particular because they are accompanied by an abnormal proliferation of megakaryocytes and platelets. We thought it would be interesting to target these cancer cells with our anti-GARP antibodies », explained Sophie Lucas. The results were conclusive... but there was a surprise! « Indeed, platelets and cancerous megakaryocytes do express GARP, but it is not because our antibodies target these cells that they are effective, it is because they target the Tregs. We didn't expect that at all! »

Référence : Lecompte et al (2022) Blood doi: 10.1182/blood.2022017097

Source : Communiqué de presse de l’UCLouvain

Illustration : by FLY:D on Unsplash