Potential Biomarker Identified for Treatment of Multiple Cancer Types

The TGF-beta cell surface receptor GARP, may be a diagnostic marker in breast cancer, colon cancer, and lung cancer.

TGF-beta is a cytokine that controls the cell cycle, and is used by regulatory T cells (Tregs) as a signal to instruct immune cells not to attack normal cells. In tumors, large amounts of TGF-beta are released to allow cancers cells to divide rapidly, and drive Tregs to suppress and attack immune cells.

Developing therapies that block TGF-beta is difficult because healthy cells are unable to function without it. However, GARP is the only known receptor that allows TGF-beta to dock on the surface of cells, helping the cells to store TGF-beta. Additionally, GARP can bind and activate TGF-beta before leaving the surface of the cells that express it.

In a study published in Cancer Research, investigators wanted to examine if GARP plays a direct role in cancer development. The investigative team found that GARP levels were much higher in biopsies of human breast, colon, and lung tumors compared with normal tissue.

From this finding, the investigators hypothesized that higher levels of GARP enabled greater storage capacity for the TGF-beta, which is needed for enhanced tumor growth, according to the study.

To determine if GARP did, in fact, have a direct role in the development of cancer, the investigators deleted the gene for GARP from mice with mammary tumors.

The results of the study showed that in the absence of GARP, breast tumors grew at a much slower rate and were less able to metastasize to the lungs. Further experiments showed increased TGF-beta signaling, tumor growth, and metastasis after the gene for GARP was inserted into mouse mammary tumor cells that expressed high levels of GARP. These findings indicated that GARP promoted both metastasis and immunosuppressive effects in breast cancer.

According to the study authors, these findings were the first clues that GARP could be a diagnostic marker for cancer, and created an opportunity to develop new treatments.

In order to grow antibodies that could potentially block it, the investigators immunized mice with human GARP. Only the 4D3 antibody directly blocked human TGF-beta from binding to GARP expressed on cell surfaces.

Although 4D2 did not prevent primary mammary tumor growth in the mice, it did suppress the spread of the tumors to their lungs. But when 4D3 was combined with cyclophosphamide chemotherapy, it curbed primary tumor growth and metastasis.

The findings indicate that combination immunotherapy with GARP antibody may boost the efficacy of standard chemotherapy in breast cancer, according to the study. However, the authors noted that GARP might also block the natural ability of Tregs to suppress the immune system, which could lead to inflammatory autoimmune reactions.

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

If GARP serves as an accurate biomarker—–given the levels increase before metastasis––it could provide the opportunity for earlier detection in other aggressive cancers increase, according to Li.

“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,” Li concluded.