Researchers have discovered a key mechanism by which tumors suppress the immune system, paving the way for more effective cancer therapies. The study reveals that exhausted T cells – immune cells that lose their ability to fight cancer over time – can be “reawakened” by blocking a critical interaction between proteins on both cancer and immune cells. This breakthrough suggests a new approach to overcome immunotherapy resistance and improve long-term treatment outcomes.
The Problem With Current Immunotherapies
Modern cancer immunotherapies have revolutionized treatment by harnessing the body’s own immune system to destroy tumors. However, these therapies don’t work for everyone, and even those who initially respond can develop resistance as their T cells become overworked. This exhaustion occurs when T cells are repeatedly exposed to cancer cells, leading them to stop attacking despite still recognizing the threat.
Dr. Jedd Wolchok, co-senior author of the study, explains, “Our findings reveal a completely new way that tumors suppress the immune system. By blocking this pathway, we can help exhausted T cells recover their strength and make existing immunotherapies work better for more patients.”
How T Cells Become Exhausted: A New Discovery
Scientists have long known that a protein called PD1 contributes to T cell exhaustion. Drugs that block PD1, known as checkpoint inhibitors, have already proven effective in treating some cancers, like melanoma. However, this study reveals another crucial factor: the CD47 protein, found on both cancer cells and T cells themselves.
The research team found that T cells increase CD47 levels when exhausted, effectively putting the brakes on their own activity. While this may sound counterproductive, it’s thought to prevent harmful inflammation. Experiments in mice showed that deleting CD47 from T cells significantly slowed tumor growth.
The Role of Thrombospondin-1 in Immune Suppression
The key to understanding how tumors exploit this process lies in a protein called thrombospondin-1, produced by aggressive cancer cells. Thrombospondin-1 binds to CD47 on T cells, reinforcing the exhaustion signal. When mice were engineered to lack thrombospondin-1, their T cells showed fewer signs of exhaustion.
“That was the real eureka moment,” says Dr. Taha Merghoub, co-senior author. “It showed us that CD47 and thrombospondin are clearly key players because eliminating either one gives you the same effect.”
Blocking Exhaustion with TAX2: A Proof of Concept
To test this interaction directly, researchers used a peptide called TAX2, designed to disrupt the connection between CD47 and thrombospondin-1. Results showed that TAX2 maintained T cell activity and slowed tumor progression in mice with melanoma or colorectal cancer.
The treated T cells remained active, released more immune-boosting signals, and infiltrated tumors more effectively. TAX2 also boosted the effectiveness of existing PD1 immunotherapy.
The Future of Cancer Immunotherapy
This discovery suggests that blocking the CD47-thrombospondin-1 interaction could enhance current immunotherapies or even serve as a standalone treatment. Researchers plan to explore combining this approach with PD1 inhibition for even greater effectiveness.
According to Dr. Merghoub, “We plan to explore this therapeutic angle.” The study was supported by multiple grants from organizations like the National Institutes of Health, the Department of Defense, and the Breast Cancer Research Foundation.
By understanding and targeting the mechanisms that cause T cell exhaustion, scientists are moving closer to a future where the immune system can effectively defeat cancer for more patients.
