New checkpoint inhibitor on the block

In Nature, Josef Penninger from IMBA and co-workers from six nations report that tetrahydrobiopterin (BH4, THB), a well-known co-factor of amino acid hydroxylases and in the synthesis of neurotransmitters such as serotonine, can switch on T cell activity and proliferation and is inhibited by kyurenine, a key metabolite in immunosuppressive physiological niches previously targeted with IDO and TDO inhibitors.

Genetic inactivation of GTP cyclohydrolase 1 (GCH1),  the rate-limiting enzyme in the synthesis of BH4,  and inhibition of sepiapterin reductase, the terminal enzyme in the synthetic pathway for BH4, severely impaired the proliferation of mature mouse and human T cells. As BH4 production in activated T cells is linked to alterations in iron metabolism and mitochondrial bioenergetics, in vivo blockade of BH4 synthesis abrogated T-cell-mediated autoimmunity and allergic inflammation. Enhancing BH4 levels through GCH1 overexpression augmented responses by T helper and cytotoxic effector T cells, increasing their antitumour activity in vivo.

Administration of BH4 to mice markedly reduced tumour growth and expanded the population of intratumoral effector T cells. Kynurenine – a tryptophan metabolite that blocks antitumour immunity via Treg activation and Teff apoptosis – inhibited T cell proliferation in a manner that can be rescued by BH4.

The new data identify GCH1, SPR and their downstream metabolite BH4  as critical regulators of T cell biology that may be readily manipulated to either block autoimmunity or enhance anticancer immunity if a therapeutic window is available. A SPR antagonist, QM385, is currently optimised for clinical testing.