Breakthrough in Cancer Treatment: Scientists Reawaken Exhausted T Cells

A new study led by researchers at Weill Cornell Medicine highlights a breakthrough in cancer treatment by identifying a molecular cue that contributes to T cell exhaustion in the immune response against tumors.

Published in Nature Immunology, the research reveals that tumors can not only evade the immune system but also alter immune cells, diminishing their ability to fight back. Co-senior author Dr. Taha Merghoub emphasizes the goal is to harness the power of exhausted T cells to revive them for cancer destruction, paving the way for more effective immune-based therapies.

The study points out that while modern immunotherapies have transformed cancer treatment, not all patients respond adequately, and even successful responses can wane as T cells become overburdened. According to co-senior author Dr.

Jedd Wolchok, this research uncovers a new mechanism through which tumors suppress the immune system, indicating that blocking this pathway may rejuvenate exhausted T cells and enhance immunotherapy effectiveness.

T cell exhaustion typically occurs during prolonged infections or persistent tumors, where T cells recognize harmful cells but stop attacking, effectively becoming 'primed' but inactive. This process, while detrimental, can prevent uncontrolled inflammation and sepsis.

Previous studies identified the surface protein PD1 as a contributor to T cell exhaustion, and existing checkpoint inhibitors targeting PD1 have shown success in cancers like melanoma. The researchers then focused on CD47, a molecule prevalent on cancer cells, hypothesizing its role in T cell exhaustion.

They discovered that activated T cells express CD47, and its levels increase significantly during exhaustion. Experiments indicated that mice lacking CD47 exhibited slower tumor growth, suggesting the exhaustion effect arises from CD47 on immune cells rather than solely from cancer cells.

Their exploration further revealed that thrombospondin-1, produced by metastatic cancer cells, interacts with CD47 to exacerbate T cell exhaustion. In experiments, mice lacking thrombospondin-1 displayed fewer exhaustion signs in their T cells.

The team developed a peptide called TAX2 to disrupt the interaction between CD47 and thrombospondin-1, resulting in maintained T cell activity and reduced tumor progression in mouse models of melanoma and colorectal cancer.

TAX2 also improved the efficacy of PD1 immunotherapy. The findings indicate that blocking the CD47-thrombospondin-1 interaction could serve as a standalone therapy and may enhance the durability of T cell responses in patients at risk of developing resistance to current immunotherapies.

The researchers plan to explore this therapeutic strategy further, aiming to develop safe and selective methods to disrupt this pathway. This innovative approach could lead to more robust, long-lasting immune therapies against cancer, as Dr.

Merghoub notes that early findings suggest a combination of inhibiting both PD1 and CD47 could significantly enhance T cell cancer destruction capabilities. The research was supported by various organizations, including the National Institutes of Health and the Cancer Research Institute.