Reduced expression of PD-L1 and IDO1 characterises early response to antimonial therapy in cutaneous leishmaniasis patients
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 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.
Wickremasinghe Renu、Kaye Paul M.、Senarathna Sujai、Madarasinghe Nayani、Seneviratne Bimalka、Lagos Dimitris、Moulik Srija、Ranasinghe Shalindra、Walrad Pegine、Dey Nidhi S.、Somaratne Vijani、Chatterjee Mitali、Reis Luiza Campos、Goto Hiro
Department of Parasitology, University of Sri JayewardenepuraYork Biomedical Research Institute, Hull York Medical School, University of YorkDepartment of Parasitology, University of Sri JayewardenepuraDermatology Unit, Teaching Hospital AnuradhapuraDeparment of Pathology, University of Sri JayewardenepuraYork Biomedical Research Institute, Hull York Medical School, University of YorkDepartment of Pharmacology, Institute of Postgraduate Medical Education and ResearchDepartment of Parasitology, University of Sri JayewardenepuraYork Biomedical Research Institute, Dept. of Biology, University of YorkYork Biomedical Research Institute, Hull York Medical School, University of YorkDermatology Unit, District General Hospital HambantotaDepartment of Pharmacology, Institute of Postgraduate Medical Education and ResearchInstituto de Medicina Tropical de S?o Paulo, Faculdade de Medicina, Universidade de S?o PauloInstituto de Medicina Tropical de S?o Paulo, Faculdade de Medicina, Universidade de S?o Paulo
医学研究方法皮肤病学、性病学基础医学
Wickremasinghe Renu,Kaye Paul M.,Senarathna Sujai,Madarasinghe Nayani,Seneviratne Bimalka,Lagos Dimitris,Moulik Srija,Ranasinghe Shalindra,Walrad Pegine,Dey Nidhi S.,Somaratne Vijani,Chatterjee Mitali,Reis Luiza Campos,Goto Hiro.Reduced expression of PD-L1 and IDO1 characterises early response to antimonial therapy in cutaneous leishmaniasis patients[EB/OL].(2025-03-28)[2025-08-02].https://www.biorxiv.org/content/10.1101/2020.02.21.959528.点此复制
评论