By Allan Mai ‘20

BH4 is an important regulator of many bodily functions. Among its most important functions are its involvement in the production of monoamine neurotransmitters, its generation of nitric oxide, and its role in pain. However, Shane Cronin and his team recently uncovered another important function of this cofactor: proliferation of T cells, which are an integral part of the immune response. Inhibitions of the rate limiting enzyme (GCH1) and the terminal enzyme in the synthetic pathway for BH4 were found to severely impair mouse and human T cell proliferation. In a converse experiment, overexpressing the rate limiting enzyme increased T cell proliferation and augmented anti-tumor activity.

To test whether hyperactivation of BH4 truly promotes anticancer immunity, the researchers injected breast cancer cells into mice to generate mammary tumors. Treatment of infected mice with BH4 slowed the growth of the tumors; in fact, the tumors showed higher frequencies of activated CD4 and CD8 cells, which are also integral parts of the immune response. To further validate these results, kynurenine, which inhibits T cell proliferation and blocks the activity of sepiapterin reductase, the terminal enzyme in BH4 synthesis, was added to the cancer line. Kynurenine treatment reduced T cell proliferation; however, addition of BH4 reversed this.

In addition to compiling data relating BH4 to T cell proliferation, Cronin and his team also linked the mechanism connecting the two molecular species to iron metabolism and mitochondrial respiration; it is for this reason that iron deficiency is associated with increased incidence of cancer. This experiment also suggests that reduced BH4 levels decrease T cell proliferation which allows a tumor to thrive in the immunocompromised environment. Therefore, inhibiting the synthesis of BH4 is one way pathogens can evade the immune system, especially the T cells, while elevating BH4 is a way to enhance immunity, especially against tumors. More studies must be completed before BH4 can be integrated into current cancer therapies, but Cronin’s experiment opens the door to a plethora of interesting possibilities.

References

1. S. Cronin, et. al., The metabolite BH4 controls T cell proliferation in autoimmunity and cancer. Nature (2018). doi: https://doi.org/10.1038/s41586-018-0701-2.  
2. Image retrieved from: https://www.pexels.com/photo/clinic-doctor-health-hospital-4154/