PT  - JOURNAL ARTICLE
AU  - Nidhi S. Dey
AU  - Sujai Senarathna
AU  - Vijani Somaratne
AU  - Nayani Madarasinghe
AU  - Bimalka Seneviratne
AU  - Luiza Campos Reis
AU  - Srija Moulik
AU  - Pegine Walrad
AU  - Mitali Chatterjee
AU  - Hiro Goto
AU  - Renu Wickremasinghe
AU  - Dimitris Lagos
AU  - Paul M. Kaye
AU  - Shalindra Ranasinghe
TI  - Reduced expression of PD-L1 and IDO1 characterises early response to antimonial therapy in cutaneous leishmaniasis patients
AID  - 10.1101/2020.02.21.959528
DP  - 2020 Jan 01
TA  - bioRxiv
PG  - 2020.02.21.959528
4099  - http://biorxiv.org/content/early/2020/02/24/2020.02.21.959528.short
4100  - http://biorxiv.org/content/early/2020/02/24/2020.02.21.959528.full
AB  - Cutaneous leishmaniasis (CL) is a disfiguring disease caused by infection with Leishmania parasites and is characterised by parasitism of the dermis and chronic inflammation. Whilst T cell responses to Leishmania are essential for both parasite clearance and disease resolution they also drive inflammation, and clinical presentation reflects the balance of these opposing activities1. Pentavalent antimonials (e.g. sodium stibogluconate; SSG) remain the first line drugs for CL, even though treatment may be protracted and painful. Although evidence from animal models indicates that an effective clinical response to antimonials requires immune-drug synergy2, little is known about how this operates in human disease. Here, we studied formalin fixed paraffin embedded (FFPE) skin biopsies from patients in Sri Lanka with CL, at presentation and during intra-lesional SSG treatment. Immune-targeted transcriptomics in a test patient cohort indicated heightened immune checkpoint pathway expression at presentation. We confirmed reduced PD-L1 and IDO1 protein expression on treatment in a second validation cohort, using digital spatial profiling and quantitative immunohistochemistry. PD-L1 and IDO1 expression on CD68+ monocytes / macrophages was positively correlated with the degree of intracellular parasitism, as determined by parasite-specific RNA FISH. Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition of T cell immunity, thus facilitating immune-drug synergism and clinical cure. We suggest a need to evaluate shorter course SSG treatment and/or the use of checkpoint inhibition as an adjunct host directed therapy (HDT) in CL.