Go to JCI Insight
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
  • Current issue
  • Past issues
  • By specialty
    • COVID-19
    • Cardiology
    • Gastroenterology
    • Immunology
    • Metabolism
    • Nephrology
    • Neuroscience
    • Oncology
    • Pulmonology
    • Vascular biology
    • All ...
  • Videos
    • Conversations with Giants in Medicine
    • Author's Takes
  • Reviews
    • View all reviews ...
    • Immune Environment in Glioblastoma (Feb 2023)
    • Korsmeyer Award 25th Anniversary Collection (Jan 2023)
    • Aging (Jul 2022)
    • Next-Generation Sequencing in Medicine (Jun 2022)
    • New Therapeutic Targets in Cardiovascular Diseases (Mar 2022)
    • Immunometabolism (Jan 2022)
    • Circadian Rhythm (Oct 2021)
    • View all review series ...
  • Viewpoint
  • Collections
    • In-Press Preview
    • Commentaries
    • Research letters
    • Letters to the editor
    • Editor's notes
    • Editorials
    • Viewpoint
    • Top read articles
  • Clinical Medicine
  • JCI This Month
    • Current issue
    • Past issues

  • Current issue
  • Past issues
  • Specialties
  • Reviews
  • Review series
  • Conversations with Giants in Medicine
  • Author's Takes
  • In-Press Preview
  • Commentaries
  • Research letters
  • Letters to the editor
  • Editorials
  • Viewpoint
  • Top read articles
  • About
  • Editors
  • Consulting Editors
  • For authors
  • Publication ethics
  • Alerts
  • Advertising
  • Job board
  • Subscribe
  • Contact
Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis
Nidhi S. Dey, … , Paul M. Kaye, Shalindra Ranasinghe
Nidhi S. Dey, … , Paul M. Kaye, Shalindra Ranasinghe
Published October 5, 2021
Citation Information: J Clin Invest. 2021;131(22):e142765. https://doi.org/10.1172/JCI142765.
View: Text | PDF
Concise Communication Immunology Infectious disease

Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis

  • Text
  • PDF
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 patients with CL 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 programmed death-ligand 1 (PD-L1) and indoleamine 2,3-dioxygenase 1 (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 with noninfected lesional CD68+ monocytes and 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 a predictor of rapidity of clinical response to SSG treatment in Sri Lanka and support further evaluation of PD-L1 as a host-directed therapeutic in leishmaniasis.

Authors

Nidhi S. Dey, Sujai Senaratne, Vijani Somaratne, Nayani P. Madarasinghe, Bimalka Seneviratne, Sarah Forrester, Marcela Montes de Oca, Luiza Campos Reis, Srija Moulik, Pegine B. Walrad, Mitali Chatterjee, Hiro Goto, Renu Wickremasinghe, Dimitris Lagos, Paul M. Kaye, Shalindra Ranasinghe

×

Figure 1

Differential expression and network analysis of genes regulated by drug treatment in lesions of Sri Lankan patients with CL.

Options: View larger image (or click on image) Download as PowerPoint
Differential expression and network analysis of genes regulated by drug ...
Immune-targeted tissue transcriptomics were conducted on tissue sections from test cohort patients comparing transcriptomes at presentation and on treatment. (A) Principal component analysis was performed to show differences between the pre- and on-treatment transcriptome of each patient based on 770 genes from the nCounter PanCancer Immunology Panel (n = 6). (B) DEGs comparing pretreatment biopsies with biopsies taken after 2 weeks on treatment (SSG). Cut off (red line) drawn at equivalent of adjusted P = 0.01 and log (fold change) of 1. (C) Top 30 genes that changed in expression on SSG treatment. (D) STRING protein-protein interaction network (https://string-db.org; ref. 22) analysis of genes listed in Supplemental Table 3 downregulated on SSG treatment. Pathways represent GO: 0072676, lymphocyte migration (red spheres), and GO: 0002684, positive regulation of immune system process (blue spheres). Top 20 genes are shown (log2 fold change ≥ 1.15) for clarity.

Copyright © 2023 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

Sign up for email alerts