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To A "T"

Aspirin could augment adoptive T cell therapy for cancer

by Sver Aune

illustration
Stylized illustration of a T cell and platelet. Illustration by Emma Vought.

Blood platelets help disguise cancer from the immune system by suppressing T cells, according to a new study by MUSC scientists featured on the cover of the May 5, 2017 issue of Science Immunology. Adoptive T cell therapy more successfully boosted immunity against melanoma when common antiplatelet drugs such as aspirin were added.

Zihai Li, M.D., Ph.D., chair of the MUSC Department of Microbiology and Immunology, is senior author on the paper. Li studies how tumors hide themselves from the immune system. His team found that platelets release a molecule that suppresses the activity of cancer-fighting T cells. That molecule, unsurprisingly, was TGF-beta, which has been recognized for decades for its role in cancer growth.

Yet this study is the first of its kind. Li and his group found that the surface of platelets has a protein called GARP, a molecular hook that is uniquely able to trap and activate TGF-beta. With GARP, platelets are the major source of activated TGF-beta that invading tumor cells use as an invisibility cloak from the immune system.

There was some prior evidence that platelets might make cancer worse. For example, patients who have excessive clotting related to their cancer almost always have a worse prognosis, according to Li.

The first clue arose when the team gave melanoma to mice with genetically defective platelets. Tumors grew much more slowly and primed T cells were much more active than in mice with normal platelets. Next, they found that human and mouse platelets with activated clotting suppressed T cell activity. Mass spectrometry revealed that the molecule with the most T cell suppression was TGF-beta.

The investigators zoomed in closer to see how platelets actually activated TGF-beta. In genetically modified mice without GARP, platelets were not able to suppress cancer-fighting T cells. This finding was confirmed in similar experiments in mice with colon carcinoma. Finally, mice with normal platelets that were given melanoma and then adoptive T cell therapy survived longer and relapsed less when aspirin and clopidogrel, two antiplatelet drugs, were added.

The study could inform future treatment of melanoma and other cancers and offers a sound reason to test antiplatelet drugs in clinical trials of adoptive T cell therapy. Li and his group also want to know if combining antiplatelet drugs with checkpoint inhibitors can improve existing treatments for melanoma. They are waiting for approval for a clinical trial to test certain checkpoint inhibitors in combination with aspirin and clopidogrel in patients with advanced cancers. Li’s trial will complement clinical trials that are already testing adoptive T cell therapy as a single treatment for cancer.

“I’m very excited about this,” says Li. “We can test simple, over-the-counter antiplatelet agents to really improve immunity and make a difference in how to treat people with cancer.”