Dey, Nidhi S, Senaratne, Sujai, Somaratne, Vijani et al. (13 more authors) (2021) Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis. Journal of Clinical Investigation. e142765. ISSN 1558-8238
Abstract
Cutaneous leishmaniasis (CL) is caused by Leishmania donovani in Sri Lanka. Pentavalent antimonials (e.g. sodium stibogluconate; SSG) remain first line drugs for CL with no new effective treatments emerging. We studied whole blood and lesion transcriptomes from Sri Lankan CL patients at presentation and during SSG treatment. From lesions but not whole blood, we identified differential expression of immune-related genes, including immune checkpoint molecules, after onset of treatment. Using spatial profiling and RNA-FISH, we confirmed reduced expression of PD-L1 and IDO1 proteins on treatment in lesions of a second validation cohort and further demonstrated significantly higher expression of these checkpoint molecules on parasite-infected compared to non-infected lesional CD68+ monocytes / macrophages. Crucially, early reduction in PD-L1 but not IDO1 expression was predictive of rate of clinical cure (HR = 4.88) and occurred in parallel with reduction in parasite load. Our data support a model whereby the initial anti-leishmanial activity of antimonial drugs alleviates checkpoint inhibition on T cells, facilitating immune-drug synergism and clinical cure. Our findings demonstrate that PD-L1 expression can be used as predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host directed therapy target in leishmaniasis.
Metadata
Item Type: | Article |
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Authors/Creators: |
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Copyright, Publisher and Additional Information: | © 2021, Dey et al. |
Dates: |
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Institution: | The University of York |
Academic Units: | The University of York > Faculty of Sciences (York) > Hull York Medical School (York) The University of York > Faculty of Sciences (York) > Biology (York) |
Depositing User: | Pure (York) |
Date Deposited: | 08 Oct 2021 12:00 |
Last Modified: | 27 Dec 2024 00:20 |
Published Version: | https://doi.org/10.1172/JCI142765 |
Status: | Published online |
Refereed: | Yes |
Identification Number: | 10.1172/JCI142765 |
Open Archives Initiative ID (OAI ID): | oai:eprints.whiterose.ac.uk:179024 |
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Filename: 142765.1_20211004093009_covered_e0fd13ba177f913fd3156f593ead4cfd.pdf
Description: Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis
Licence: CC-BY 2.5