Thrombin, a blood-clotting protein, contributes to cancer growth by overpowering the immune system

The connection between blood-clot formation and cancer progression has been known for decades. In fact, the Centers for Disease Control and Prevention reports that every year about 900,000 Americans are affected by a blood-clotting problem, and one in five of those cases are cancer related. 

A recent Science Translational Medicine article by Medical University of South Carolina (MUSC) and Ohio State University researchers offers new insight into how clotting contributes to cancer. 

“Cancer has been described as a wound that never heals and will therefore initiate blood-clotting events that recruit many platelets.” 

-- Dr. Alessandra Metelli

The senior author of the study, Zihai Li, M.D., Ph.D., former chairman of the MUSC Department of Immunology and Microbiology and heavily involved in research at the MUSC Hollings Cancer Center, is now the Klotz Memorial Chair in Cancer Research and founding director of the Pelotonia Institute for Immuno-Oncology at the Ohio State University James Comprehensive Cancer Center. Alessandra Metelli, Ph.D., first author of the study, worked in Li’s laboratory when he was at MUSC and is now investigating the role of monocytes and macrophages in cancer immunotherapy at MUSC in the laboratory of Hollings cancer researcher Carsten Krieg, Ph.D., assistant professor in the Department of Microbiology and Immunology.

“Cancer has been described as a wound that never heals and will therefore initiate blood-clotting events that recruit many platelets,” said Metelli. “We already knew that these platelets release a massive number of pro-tumor factors that enhance cancer growth.” 

One of the most abundant factors released by platelets is called transforming growth factor beta-1 (TGF-b1). It is known to suppress the functions of the immune system, our first defense against malignancies, thereby supporting the growth of cancer cells. 

In the report, Metelli and her colleagues at MUSC Hollings Cancer Center and the Ohio State University found that thrombin, a biological molecule that promotes blood clotting, is also responsible for releasing TGF-b1 from platelets. In doing so, they uncovered a mechanism by which clotting contributes to cancer. This finding could help lay the foundation for a new approach to treating cancer patients who do not respond to immunotherapy.  

“Immunotherapy does not work for every patient because there are various biological pathways that block the proper function of our immune cells,” explained Li. “In this study, we discovered that by targeting the blood clot formation pathway with clinically available drugs, we could enhance our immune cells and stop cancer growth.” 

For their study, the research team chose dabigatran, a blood thinner that prevents clots by inhibiting thrombin. It significantly decreased TGF-b1production from platelets, enhanced the immune system against cancer and prevented tumor growth in a colorectal cancer mouse model.

Mechanistically, this study showed that thrombin releases TGF-b1 from platelets by cleaving a molecule known as GARP, which acts as a TGF-b1 receptor. 

“The cleavage of GARP by thrombin releases TGF-b1 from the platelet surface,” explained Metelli. “The released TGF-b1 is then free to support the growth of the cancer cells by suppressing the normal functioning of immune cells.” 

“These findings could one day help physicians to preselect cancer patients with poor immune systems or blood-clotting problems so as to receive this blood-thinner combination therapy."

 

-- Dr. Zihai Li

To verify that thrombin was truly responsible for splitting GARP apart and releasing the active form of TGF-b1, the researchers looked closely at the structure of GARP and found binding sites for thrombin. They then showed that when thrombin inhibitors, such as dabigatran, are used, the GARP protein remains intact and TGF-b1production from platelets is significantly reduced. 

 To make their study clinically relevant, the team combined dabigatran with an immune treatment called anti-PD-1 immunotherapy. Anti-PD-1 immunotherapy is now used as a first line of defense against multiple malignancies. It “takes the brakes” off the immune system, enabling it to fight and kill cancer cells. 

Using preclinical models of colorectal and triple-negative breast cancer, the team showed that treatment with either dabigatran or anti-PD-1 reduced cancer growth. However, the combination of the two therapies produced the strongest treatment response by reducing tumor burden and metastasis.

Based on this work, the team proposes to combine anti-PD-1 immunotherapy with dabigatran as an investigational treatment for cancer patients who do not respond to anti-PD1 immunotherapy alone. 

 Li believes that the findings have strong clinical relevance. 

“These findings could one day help physicians to preselect cancer patients with poor immune systems or blood-clotting problems so as to receive this blood-thinner combination therapy,” explained Li. “We hope to move forward in developing a cancer clinical trial to test this combination therapy.”