Antiplatelet Drugs Could Boost Effectiveness of Adoptive T Cell Therapy – Bioscience Technology

Platelets, small fragments of large cells that are a very abundant component of blood, and best known for their role in blood-clotting, help hide cancer from the immune system by suppressing T cells, according to a new study.

Now, in preclinical studies, researchers led by Zihai Li, M.D. Ph.D., chair of the Medical University of South Carolinas Department of Microbiology and Immunology found adoptive T cell therapy was more effective against melanoma when combined with common platelet-inhibitors, such as aspirin.

A disorder known as thrombocytosis, where a patient has excess platelet product, has been associated with the progression of multiple cancer types. However, how platelets change T cell immunity to encourage tumor growth was not well understood and this study sought to investigate the role more closely.

A molecule called TGF-beta is linked to suppression of the cancer-fighting activity of T cells, the study found. Immunologists have been studying TGF-beta for more than 30 years as it regulates many aspects of the immune system.

More importantly, Lis team found a protein called GARP, on the surface of the platelets, acts like a molecular hook that binds to and activates TGF-beta.

We found for the first time that the GARP, TGF-beta complex is a key mechanism utilized by platelets to subvert T cell immunity, Li said.

The first indication that the bodys clotting system might play a role in suppressing cancer-fighting T cells, was when scientists observed melanoma mouse models with genetically defective platelets.

In the mice with genetically defective platelets, T cells that were isolated and then primed to recognize tumor cells were much more active when reinjected into the mice, and tumors grew significantly more slowly than in animals with normal platelets.

Platelets and T cells isolated from mouse and human blood were observed, and both showed the T cell response was suppressed by platelets with activated clotting activity. Using mass spectrometry, the team identified the molecule with the most T cell suppression was TGF-beta.

Next, Li investigated what would happen if the platelets couldnt activate TGF-beta. They genetically modified mice without the molecular hook GARP, and found that once the platelets didnt have the ability to grab and activate TGF-beta, they could not suppress the cancer-fighting T cells. The T cell immunotherapy was more effective at controlling melanoma.

In a final experiment, the team tested melanoma models of mice with normal platelets who received adoptive T cell therapy, in combination with two antiplatelet drugs, aspirin and clopidogrel. They found that animals who received the antiplatelet drugs survived longer and relapsed less.

One popular form of current immunotherapy is so-called checkpoint inhibitors. Li and his team are about to launch a clinical trial to test the combination of checkpoint inhibitors and aspirin and clopidogrel for advanced cancers.

Im very excited about this, Li said. We can test simple, over-the-counter antiplatelet agents to really improve immunity and make a difference in how to treat people with cancer.

The findings were published May 5 in Science Immunology.

More:
Antiplatelet Drugs Could Boost Effectiveness of Adoptive T Cell Therapy - Bioscience Technology