Columbus, Ohio - A new study led by researchers at The Ohio State University Comprehensive Cancer Center - Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSUCCC - James) reveals how a clotting protein and blood platelets can promote cancer progression and suppress immune responses to cancer.
The findings show how thrombin, a clotting protein in the blood, causes blood platelets to release transforming growth factor-beta 1 (TGF-b1), which is known for promoting disease progression in breast, prostate, colorectal and other cancers, and for suppressing immune-system responses to cancer.
Additionally, TGF-b1 is a leading cause for the failure of immune therapies such as PD1 inhibitors in cancer patients. This study may offers a new explanation for what causes tumors to resist immune therapies and become sensitive to the therapeutic agents.
The researchers used animal models to show that inhibiting thrombin activity prevents the release of TGF-1b and makes tumors that were resistant to anti-PD-1 immunotherapy susceptible to these agents.
The findings are reported in the journal Science Translational Medicine.
"In this study, we describe a direct connection between thrombin and TGF-b1, a cytokine that promotes tumor progression and suppresses the ability of immune cells to attack the tumor," says principal investigator Zihai Li, MD, PhD, a professor in the Division of Medical Oncology at Ohio State and the founding director of the Pelotonia Institute for Immuno-Oncology (PIIO) at the OSUCCC - James. Li also holds the Klotz Memorial Chair in Cancer Research at The Ohio State University College of Medicine
"We also show that systemically interfering with this mechanism prevents the release of TGF-1b and leads to changes in the tumor microenvironment that are favorable to anticancer immune responses," says Li, who is a member of the OSUCCC - James Translational Therapeutics Program.
Li notes that cancer is similar to an unhealed wound that constantly activates the coagulation pathway and generates high concentrations of thrombin in and around a tumor. That, in turn, causes chronic platelet activation and release of TGF-1b.
"TGF plays important roles in cancer development," Li says. "Specifically, TGF-b1 alters the tumor microenvironment in ways that protect cancer cells from attack by immune cells."
Research has shown that inhibiting TGF-b1 enhances cancer immunotherapy, Li adds. "If we can effectively inhibit TGF-b1 maturation or function, it should open new avenues for cancer therapy."
For this study, Li and his colleagues used blood samples from cancer patients, genetic analyses, cell lines and animal models to investigate the mechanism underlying the release of mature TGF-1b and the implications of blocking that release as a means of cancer immunotherapy.
Key findings include:
- Thrombin cleaves a molecule called GARP (glycoprotein A repetitions predominant) that is found on the surface of platelets;
- GARP cleavage leads to the release of mature TGF-1b from platelets;
- This cleavage is required to activate platelet TGF-b1;
- Blocking thrombin using the inhibitor dabigatran etexilate greatly altered the tumor microenvironment and increased the number and activity of tumor-infiltrating T cells, natural killer cells and neutrophils.
"Overall, our study reveals a mechanism of cancer immune evasion that involves thrombin-mediated GARP cleavage and the release of TGF-b1 by platelets," Li says. "It also suggests that blocking GARP cleavage could be an effective therapeutic strategy for overcoming cancer's resistance to immunotherapy."
Funding for this study was provided by grants from the National Institutes of Health (AI077283, CA188419, CA213290, DK105033, and CA186866).
Other researchers involved in this study were Bill X. Wu, Brian Riesenberg, Anqi Li, David P. Carbone and Yiping Yang, The Ohio State University; Alessandra Metelli, Silvia Guglietta, Catherine Mills, Saleh Rachidi, Carsten Krieg, Mark P. Rubinstein, Shaoli Sun, Michael B. Lilly, Amy H. Wahlquist and Bei Liu, Medical University of South Carolina; and John D. Huck, Daniel T. Gewirth and Hauptman Woodward, Medical Research Institute, Buffalo, NY.
To learn more about the Pelotonia Institute for Immuno-Oncology, visit cancer.osu.edu/piio.
About the OSUCCC - James
The OSUCCC - James strives to create a cancer-free world by integrating scientific research with excellence in education and patient-centered care, a strategy that leads to better methods of prevention, detection and treatment. Ohio State is one of only 51 National Cancer Institute (NCI)-designated Comprehensive Cancer Centers and one of only a few centers funded by the NCI to conduct both phase I and phase II clinical trials on novel anticancer drugs sponsored by the NCI. As the cancer program's 356-bed adult patient-care component, The James is one of the top cancer hospitals in the nation as ranked by U.S. News & World Report and has achieved Magnet® designation, the highest honor an organization can receive for quality patient care and professional nursing practice. At 21 floors and with more than 1.1 million square feet, The James is a transformational facility that fosters collaboration and integration of cancer research and clinical cancer care. For more information, visit cancer.osu.edu.