Researchers from the Georg-Speye-Haus in Germany have identified a new approach to colorectal cancer (CRC) therapy – one based around a metabolite product of pomegranates. The paper, published in the journal Immunity, demonstrates how urolithin A (UA) could be used to prevent T cell exhaustion and improve the effectiveness of cancer therapy.
The environmental context of CRC
Colorectal cancer is 3rd most diagnosed cancer worldwide and has high mortality rates. The progression of this cancer type is strongly linked to the tumour microenvironment and the presence of T cells – particularly CD8+ T cells and memory T cells.
Researchers have previously shown that mitophagy (the recycling and renewal of mitochondria) in mouse epithelial cells can increase CD8+ T cells in early intestinal tumorigenesis, but the efficacy of immunotherapy is limited by T cell exhaustion.
One factor driving this exhaustion is metabolic changes in mitochondria functioning – effector tumour-infiltrating lymphocytes show decreased mitophagy. Therefore, the team wondered whether increasing mitophagy could augment anti-tumour immunity. Another potential route would be to increase the presence of T memory cells. T memory stem cells have self-renewal properties and exhibit prolonged survival, meaning they help prevent T cell exhaustion and promote effective anti-tumour T cell responses in the fight against cancer.
A pomegranate a day keeps the doctor away?
T memory cells can be expanded by urolithin A (UA), a molecule produced by our gut microbiome in response to foods rich in ellagitannins (like pomegranate). However, the conversion to UA depends on having the right gut microbiome, and it appears that as we age, we tend to produce less UA. In fact, older adults produce less than half the UA that younger individuals do.
High UA diets have already been shown to reduce the effects of aging and to increase recovery of muscle function in mice with Duchenne muscular dystrophy. UA has also been shown to reduce inflammation.
To demonstrate the therapeutic potential of UA, the team used UA food supplements in a mouse preclinical model and showed how this limited tumour growth. They then supplied UA in vitro in human T cells. They found that UA induces MHC-I upregulation on tumour epithelia and promotes expansion of T memory stem cells.
Moving to the clinic
The team’s results support the use of UA in combination with immune checkpoint blockade or in adoptive T cell therapy. “Our findings are particularly exciting because the focus is not on the tumour cell but on the immune system, the natural defence against cancer,” said Dominic Denk, first author of the study. “This is where reliable therapeutic approaches are still lacking in the reality of colorectal cancer patients. By possibly improving combination therapy with existing immunotherapies, the study opens up meaningful possibilities for further application in the clinic. We hope to use this to sustainably improve the therapy of colorectal cancer, but also of other cancers.”
There is still some work needed to identify the exact mitochondrial target driving this process, but more research is on the horizon. Future clinical trials will explore whether oral UA supplements or in vitro treatment of leukocytes can be used for more effective tumour therapy in CRC patients. Florian Greten, Director of the Georg-Speye-Haus, added: “We are very pleased that we can now quickly transfer our results to the clinic and look forward with excitement to the upcoming clinical trials.”
