A pair of recent studies from the laboratory of Bin Zhang, MD, PhD, the Johanna Dobe Professor of Cancer Immunology, have uncovered new details about critical biological processes that may help improve cancer treatments.
According to Zhang, the two studies shed new light on improving immune responses in cancer and will help fine-tune existing treatments.
Re-Charging T-cells Exhausted by Cancer
In the first study, published in the Journal of Clinical Investigation, Zhang and his collaborators uncovered a crucial mechanism that enables tumors to evade the body’s defenses.
“In cancer, in addition to inhibitory receptors, activated T-cells also exhibit upregulation of numerous co-stimulatory receptors like 4-1BB,” said Zhang, who was senior author of the study. “There’s a longstanding research interest in agonizing these co-stimulatory pathways.”
In the study, scientists first triggered the 4-1BB signaling to boost T-cell activity. They found that the increased survival and expansion of T-cells with 4-1BB stimulation required two key metabolic molecules needed to regulate oxidative stress, GSH and GPX4, but were more susceptible to exhaustion over time.
Next, scientists genetically deleted A2BR in mice – a receptor that suppresses immune responses causing exhaustion – while also being regulated by 4-1BB signaling. They found that levels of GSH and GPX4 stabilized and exhaustion decreased without A2BR upon 4-1BB stimulation.
This metabolic reprogramming not only improved T-cell survival but also reduced T-cell exhaustion, a common challenge in immunotherapy.
“We want to maximize T-cell activity in the context of cancer,” Zhang said. “This is one way to potentiate T-cell activity. It’s like a car, when you push the gas pedal and don’t touch the brake.”
By fine-tuning the metabolic processes that govern T-cell function, Zhang said he hopes to create more durable and effective cancer treatments.
“If you remove the A2BR, either through genetic ablation or small-molecule inhibitors, you can enhance the GSH metabolism activity,” Zhang said. “The findings cross different mouse tumor types, including triple-negative breast cancer, melanoma and lung cancer. We have all this evidence to suggest it works beautifully.”
Building off these findings, Zhang said he and his colleagues will work to develop gene editing and cell therapy to work alongside existing immunotherapies for cancer.
“We think this combination strategy can actually make T-cells fully revived and survive longer against the tumor cells,” he said.
The study was supported by National Institutes of Health grants CA222963, CA250101 and 643 CA290743. Additional funding was provided by the Department of Defense Breast Cancer Research Program Breakthrough Award and Melanoma Research Alliance Established Investigator Award.
Regulating Immune Cells to Treat Cancer
In a separate study published in Nature Communications, a team of scientists identified a method to revive exhausted immune cells in cancer.
Despite recent advancements in cancer therapies, some tumors remain under the radar of the body’s immune system cells, hindering immunotherapies.
“We were interested in how CD73, an emerging checkpoint molecule, is regulated and how we could improve immune therapy in the context of cancer,” said Zhang, who was co-senior author of the study.
In the study, investigators employed advanced multiomic spatial analyses on tumors from triple-negative breast cancer tissue samples. They found that the accumulation of MGAT1—an enzyme that plays a vital role in protein folding other vital cellular functions—led to the suppression of T-cells. This suppression makes tumors resistant to current immunotherapies, preventing the body’s natural defenses from fighting the cancer.
Scientists found that MGAT1 does this by influencing another molecule, CD73, which prevents immune cells—specifically CD8+ T cells—from effectively killing the cancer cells.
Normally, CD73 sits on the surface of tumor cells, where it works to suppress the immune system. When MGAT1 is overactive, it helps CD73 move more easily to the tumor’s surface by chemically modifying it. This leads to an increase in CD73 levels, making tumors even better at evading detection, according to the findings.
“We found that MGAT1 actually caused the abnormal CD73 upregulation in cancer cells,” Zhang said.
Finally, investigators used a newly developed inhibitor, W-GTF01, and found that it successfully blocked interactions between MGAT1 and CD73, reversing immune suppression and restoring the ability of CD8+ T cells to attack the tumors.
The tumors were then more susceptible to current immunotherapies, according to the findings.
This discovery holds promise for triple-negative breast cancer, which is notoriously aggressive and difficult to treat, Zhang said.
“We identified a small molecule that can interrupt the interaction between MGAT1 and CD73,” Zhang said. “Therefore, this can influence the downstream immunosuppressive activity and basically revive anti-tumor immune responses.”
Moving forward, Zhang and his collaborators will work to develop the approach further and move toward clinical trials, he said.
The study was supported by National Institutes of Health grants R01CA222963, R01CA250101 and R01CA258857.
Zhang is also a co-leader of the Tumor Environment and Metastasis Program and a co-leader of Cancer Immunotherapy Initiative at the Robert H. Lurie Comprehensive Cancer Center of Northwestern University and a member of the Center for Human Immunobiology.
