New Approach to Harnessing TGF-Beta Opens Door for Immunotherapy Development

New Approach to Harnessing TGF-Beta Opens Door for Immunotherapy Development

Researchers have come up with a new solution to an old cancer problem, by developing antibodies that prevent TGF-beta signaling only on cancer cells. The discovery was made possible with the realization that cancer cells use a specific receptor to harness the power of the cytokine.

Early studies showed that the antibody prevented metastases in mice with breast tumors, and when used together with chemotherapy, the approach was effective in also suppressing the main tumor.

The study, “Surface Expression of TGFβ Docking Receptor GARP Promotes Oncogenesis and Immune Tolerance in Breast Cancer,” was published in the journal Cancer Research.

The cytokine TGF-beta is a crucial component of the immune system. Regulatory T-cells use it to prevent other immune cells from attacking the body’s own cells. But, as happens with many other molecules with an important function, tumors hijack TGF-beta for their own purposes.

Aggressive tumors tend to produce large amounts of the cytokine, which allows the tumor to grow. The signaling also tells regulatory T-cells to orchestrate a suppression of any immune attack directed at the tumor.

But earlier attempts to prevent TGF-beta signaling have met a substantial obstacle; healthy cells also need TGF-beta, so blocking it in the entire body is not an option.

In an attempt to get around the problem, the research team at the Medical University of South Carolina (MUSC) decided to take a closer look at GARP, a receptor that allows the cytokine to dock at the cell surface, and is used by cells to store latent TGF-beta. Although earlier studies have shown that the gene coding for GARP is unusually active in breast cancer, the receptor has not been studied in this context before.

The team analyzed tumor tissue from breast, lung, and colon cancer patients. As suspected, they found higher GARP levels than in healthy tissue.

“TGF-beta is an old story. The new spin is that there is a docking receptor for TGF-beta that increases the activity of the cytokine, and this molecule is called GARP,” Zihai Li, MD, PhD, chair of the Department of Microbiology and Immunology at the MUSC Hollings Cancer Center and the study’s senior investigator, said in a press release.

Deleting the GARP gene from mice with breast tumors did not eradicate the tumors, but the cancer grew more slowly, and could not spread to the lungs. Likewise, inserting the GARP gene into a mouse tumor increased both tumor growth and the metastasis rate of the cancer — features linked to an increased TGF-beta signaling.

But the team went further than just using experimental methods for blocking GARP in mice. Using human GARP to make mice produce antibodies, they could identify one antibody that prevented TGF-beta from binding to the receptor.

While the antibody did not hamper the growth of breast tumors in mice, it prevented metastases formation. And when the team treated the mice with the antibody together with cyclophosphamide chemotherapy, the treatment was effective against both the original tumor and metastases.

“This discovery is fundamentally important to how TGF-beta utilizes GARP to promote cancer and down-regulate the immune system, but it also creates an opportunity for both diagnostics and therapeutics,” said Li.

The treatment, however, has a potential downside, as it may interfere with the actions of regulatory T-cells. In this way, an environment that is more permissive of autoimmune actions could be created.

“Clinically, some of the proven immunotherapies do induce some degree of autoimmunity,” said Li. “When cancer is cured and patients stop immunotherapy, the autoimmune manifestations completely disappear as well.”

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