In our recent newsletter (issue 2), we talked about the importance of tryptophan (Trp) starvation in cancer immunobiology, owing much of its initial discovery as a physiological phenomenon in maternal-fetal rejection. We now know that Trp depletion via IDO upregulation leads to IDO-AhR mediated suppression of immune activity. From an immune cell perspective, this mechanism is highly undesirable but presents a new insight that perhaps targeting immune cells to overcome Trp depletion may improve cancer prognosis. Recently, published in Nature, Abhijeet Pataskar and colleagues present a new mechanistic function of Trp depletion – tryptophan-to-phenylalanine (Trp-to-Phe) ‘substitutants.’
What is Trp-to-Phe substitutant? Pataskar and colleagues showed that depleting Trp via interferon-gamma treatment can result in codon reassignment of Trp to other amino acids. They further showed that the action of codon reassignment led to a preferential increase in Phe as substitutants driven by tryptophanyl-tRNA synthetase (WRS). Thus, the name Trp-to-Phe substitutants. You may want to gain more insight into the mechanism here.
Why is this mechanism important? By identifying this new phenomenon, the study showed that substitutants mediated by Trp depletion can lead to potent T cell recognition, thereby destroying cancer cells. Moreover, the study also showed that Trp-to-Phe substitutants were highly abundant in multiple cancer types. Hence, apart from being a physiological process in allograft rejection, Trp depletion in the context of cancer may be a physiological process to hinder cancer formation, which is beneficial to the host.
What is the significance to the Trp research community? On one hand, Trp depletion-mediated immunotolerance used by cancer cells to overcome immune cells is detrimental to the host. Yet, on the other hand, Trp-depletion-mediated Trp-to-Phe substitutants can have an opposing immune effect that is beneficial to the host. Further study leveraging on both mechanisms targeting cancer is warranted.