21 22 23 24 2 Cutaneous leishmaniasis (CL) is a disfiguring disease caused by infection with 25 Leishmania parasites and is characterised by parasitism of the dermis and chronic 26 inflammation. Whilst T cell responses to Leishmania are essential for both parasite 27 clearance and disease resolution they also drive inflammation, and clinical presentation 28 reflects the balance of these opposing activities 1 . Pentavalent antimonials (e.g. sodium 29 stibogluconate; SSG) remain the first line drugs for CL, even though treatment may be 30 protracted and painful. Although evidence from animal models indicates that an 31 effective clinical response to antimonials requires immune-drug synergy 2 , little is known 32 about how this operates in human disease. Here, we studied formalin fixed paraffin 33 embedded (FFPE) skin biopsies from patients in Sri Lanka with CL, at presentation 34 and during intra-lesional SSG treatment. Immune-targeted transcriptomics in a test 35 patient cohort indicated heightened immune checkpoint pathway expression at 36 presentation. We confirmed reduced PD-L1 and IDO1 protein expression on treatment 37 in a second validation cohort, using digital spatial profiling and quantitative 38 immunohistochemistry. PD-L1 and IDO1 expression on CD68 + monocytes / 39 macrophages was positively correlated with the degree of intracellular parasitism, as 40 determined by parasite-specific RNA FISH. Our data support a model whereby the 41 initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition of T 42 cell immunity, thus facilitating immune-drug synergism and clinical cure. We suggest a 43 need to evaluate shorter course SSG treatment and/or the use of checkpoint inhibition 44 as an adjunct host directed therapy (HDT) in CL. 45 46 One billion people are thought to be at risk of leishmaniasis, a group of diseases caused by 47 infection with protozoan parasites of the genus Leishmania and transmitted by phlebotomine 48 sand flies 3-5 . Approximately 600,000 -1 million new cases of CL occur, with a broad global 49 3 distribution, often leading to stigma and reduced life chances and placing a burden on health 50 services 6,7 . Treatment options for CL have changed little in over 70 years, since pentavalent 51antimonial drugs were first introduced, and there are scant new treatments on the horizon 8,9 . 52 Sri Lanka is endemic for CL 10 with the first autochthonous case being reported in 1992 11 . 53Sri Lankan CL is caused by Leishmania donovani zymodeme MON-37 12-14 , usually 54 associated with visceral leishmaniasis. Current treatment for CL in Sri Lanka involves 55 weekly intra-lesional or daily intra-muscular administration of SSG, with or without 56 cryotherapy, based on the site and size of the lesion and response to treatment. Cure often 57 takes many months, and some patients may fail to respond completely or withdraw from 58 treatment 15 . It is widely proposed that immune-drug synergy is required for fully effective 59 treatment in leishmaniasis and that host directed...