Reduced expression of PD-L1 and IDO1 characterises early response to antimonial therapy in cutaneous leishmaniasis patients

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 activities 1 . 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 synergy 2 , 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.