The fungal pathogen Candida albicans exploits the immune checkpoint receptor TIGIT to evade the immune response

Candida albicans is a commensal member of the human microbiome. However, under certain conditions it can turn pathogenic and is actually the most common human fungal pathogen. Such infection can be as common and unpleasant as vaginal yeast infection, the most common fungal infection, or as deadly as disseminated candidiasis, one of the five leading hospital acquired infections. Sadly, current treatments are very limited, and half the patients with blood-borne Candida infections die.

Natural Killer (NK) cells are innate lymphoid cells. They classically recognize and eliminate dangerous cells such as cancerous or virally-infected cells. However, recent evidence indicate that NK cells can also directly kill fungi, but it is largely unknown how NK cells kill fungi and whether fungi can evade NK cell attack.

To investigate whether fungi can evade immune cell recognition we used a library of recombinant NK receptors. We identified the immune checkpoint receptor, TIGIT, as one of the receptors that was recognized by C.albicans. TIGIT is an inhibitory receptor expressed on NK and T cells. TIGIT inhibits immunity under various conditions, and checkpoint anti-TIGIT antibodies are currently being tested in clinical trials as novel cancer immunotherapies.

We demonstrated that anti-TIGIT antibodies enhance NK and T cell activity against C.albicans both in-vitro and in vivo.

In conclusion, we present the first receptor-mediated fungal immune evasion mechanism, and specifically show that C.albicans exploits TIGIT to evade the anti-fungal immune response. Furthermore, we show for the first time that checkpoint therapy can be harnessed for treatment of deadly fungal infections.