Platelets do more than promote clotting. They weaken one of the body’s immune defenses against cancer. Unfortunately, platelets tend to work against the immuno-oncology treatments that try to strengthen T-cell attacks on cancer.
Platelets, new research indicates, suppress T-cell immunity against cancer by expressing a transmembrane protein, the glycoprotein A repetitions predominant (GARP) receptor. Platelet GARP can snag a growth factor, transforming growth factor-β (TGFβ), and thereby promote cancer. When GARP binds with TGFβ, the latter can become activated and then convert effector T cells, which normally attack cancer with an inflammatory reaction, into regulatory (suppressor) T cells, which turn off the inflammatory reaction.
The new findings appeared May 5 in the journal Science Immunology, in an article entitled “Platelets Subvert T Cell Immunity against Cancer via GARP-TGFβ Axis.” This study expands on earlier findings that indicated platelets, in cancer-associated thrombocytosis, might make cancer worse.
“An unbiased biochemical and structural biology approach established TGFβ and lactate as major platelet-derived soluble factors to obliterate CD4+ and CD8+ T cell functions,” wrote the article’s authors. “Moreover, we found that platelets are the dominant source of functional TGFβ systemically as well as in the tumor microenvironment through constitutive expression of the TGFβ-docking receptor GARP rather than secretion of TGFβ per se.”
Scientists have known for several years that certain cancers suppress T cells to avoid the immune system. That is why adoptive T-cell therapy is one of the most promising advances in modern cancer treatment. It is a type of immunotherapy that awakens the immune system by retraining a patient's T cells to recognize their cancer. T cells are isolated from a patient's blood and retrained, or “primed,” to recognize tumor cells. They are then injected back into the patient's bloodstream where they can now hunt and fight cancer.
In the current study, scientists have shown that genetic targeting of platelets enhances adoptive T-cell therapy of cancer. “Platelet-specific deletion of the GARP-encoding gene Lrrc32,” the authors of the Science Immunology article indicated, “blunted TGFβ activity at the tumor site and potentiated protective immunity against both melanoma and colon cancer.”
This work, which was carried out by scientists based at the Medical University of South Carolina, revealed the mechanism behind platelets’ activation of TGFβ. The scientists showed that in genetically modified mice without GARP, the molecular hook on the surface of platelets, adoptive T-cell therapy was more successful at controlling melanoma. This meant that platelets without the ability to grab and activate TGFβ were not able to suppress cancer-fighting T cells. Similar experiments confirmed this result 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 researchers noted that antiplatelet drugs by themselves were not successful in combating melanoma in their experiments.
This 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. In patients with melanoma or other cancers, adoptive T-cell therapy may be successful if highly available platelet-blocking drugs such as aspirin are added to the treatment. However, the current standard of care for melanoma is not adoptive T-cell therapy, but rather so-called checkpoint inhibitors.
The team at the Medical University of South Carolina, which was led by Zihai Li, M.D., Ph.D., want to know if combination therapy with antiplatelet drugs could improve existing cancer treatment. They are waiting for approval to begin a clinical trial that will test certain checkpoint inhibitors in combination with aspirin and clopidogrel for the treatment of patients with advanced cancers. Dr. 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,” said Dr. 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.”