A protein called FGL1 is a major inhibitory signal that blocks the immune system from fighting certain cancers, a team led by researchers at Yale Cancer Center (YCC) found.

But prior to this study, many scientists believed another molecule was the main trigger for the same immune suppressor pathway, and potential antibody therapies targeting this molecule have already entered clinical trials. 

The discovery highlights the importance of getting a solid understanding of the biology behind new therapeutic targets before moving into clinical trials.

The study, “Fibrinogen-like Protein 1 Is a Major Immune Inhibitory Ligand of LAG-3,” was published in the journal Cell.

LAG-3 is an immune checkpoint protein — a molecule that keeps the immune system from acting — primarily found at the surface of activated T-cells, a kind of specialized white blood cell key to helping fight infections and cancer.

As a checkpoint protein, LAG-3 shuts down the growth and activity of T-cells. Some tumors exploit this mechanism for their own benefit: By stimulating LAG-3, they apply a “brake” on T-cells to shield themselves from being detected and attacked.

Prior studies have suggested that a surface protein called MHC class II (MHC-II) is the major “ligand” molecule that cancer cells use to connect to and turn on the inhibitory signals of LAG-3.

Encouraged by the success of checkpoint inhibitors in fighting some cancers, many companies are developing antibodies that block the LAG-3-MHC-II interaction, including Tesaro (TSR033), Novartis (LAG525), Bristol-Myers Squibb (relatlimab) and F-star (FS118). The safety and efficacy of these candidate immunotherapies are being evaluated in trials for several advanced cancers.

However, it still “remains controversial whether MHC-II is solely responsible for the inhibitory function of LAG-3,” researchers noted. In fact, prior studies using tumor models have suggested that a mechanism independent of MHC-II is involved in the LAG-3-mediated shutdown of T-cell anti-tumor activity.

Building on this knowledge, the scientists at YCC looked for other ligands that could connect to and mediate the immune-suppressing signals of LAG-3. The work was led by Lieping Chen, who pioneered research on PD-1/PD-L1 pathway — one of the main pathways targeted by current checkpoint inhibitors to treat cancer.

After screening LAG-3 binding proteins from an array of thousands of cell surface molecules, Chen and his colleagues found that a protein called fibrinogen-like protein 1 (FGL1) is a major ligand of LAG-3.

Under normal conditions, FGL1 is released by the liver in low levels, but many cancer types can  produce it in abundance.

Consistent with an important role of FGL1 in cancer immunity, researchers observed that treatment with a monoclonal antibody (mAb) that blocked the interaction of FGL1 and LAG3 boosted T-cell activity against cancer cells in a mouse model of skin cancer (melanoma). Under this treatment, mice survived longer and tumor growth was delayed.

Next, examining human cancer databases, researchers found that FGL1 is highly expressed in multiple human solid tumors, including lung cancer, prostate cancer, melanoma, and colorectal cancer, compared to normal tissue.

Importantly, the data showed that higher levels of FGL1 in the plasma are linked to a poor prognosis (shorter overall survival) and resistance to anti-PD-1/PD-L1 therapy in patients with advanced lung cancer and melanoma.

These results show that FGL1 may constitute a new target for immune modulation and a potential biomarker to predict the outcome of anti-cancer therapies.

“We need to pay attention to the fundamentals of FGL1/LAG-3 interaction before we can develop efficient drugs for LAG-3 cancer immunotherapy,” Chen, MD, PhD, co-director of the Cancer Immunology Program at YCC, United Technologies Corporation Professor in Cancer Research, and senior author of the study, said in a press release.

Although antibodies that block MHC-II binding have moved to clinical trials, “FGL1 is the major ligand for immunosuppression, and designing LAG-3 drugs to block the MHC-II ligand only could be problematic,” he said.

Preliminary data of such trials “showed minimal or modest effect.” A possible reason for such results could be that these immunotherapies do not block FGL1 binding, leading to an incomplete blockade of LAG-3-mediated suppression.