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.
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Concise Communication Immunology Infectious disease

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

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

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Figure 3

Immunofluorescence analyses of PD-L1 in infected and uninfected cells.

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Immunofluorescence analyses of PD-L1 in infected and uninfected cells. D...
Dual IHC-FISH using an Amastin probe was performed on pretreatment sections of patients enrolled in the validation cohort. (A) A 400× confocal image showing infection of PD-L1+CD68+ (arrows) and PD-L1–CD68+ (arrowhead) cells. Scale bar: 50 pixels. (B) Relationship between PD-L1 expression and parasite burden (Amastin dot count). Scattergram from a representative patient (P24 at presentation) showing Amastin+ low (cyan), medium (red), and high (green) PD-L1–expressing cells with respect to parasite abundance. (C) Fluorescence intensity distributions of infected and uninfected PD-L1 cells. (D) Mean fluorescence intensity of PD-L1 expression on Amastin– cells compared with Amastin+ cells from representative patient P24. The upper and lower whisker represents highest and lowest value that is within 1.5 times the interquartile range. n = 9159 parasite positive cells and n = 41520 parasite negative cells. Significance score was generated using Wilcoxon signed rank test. (E) PD-L1 expression on Amastin+PD-L1+ cells versus Amastin–PD-L1+ cells (n = 7 patients). Significance score was generated using Student’s 2-tailed paired t test after testing for normality using Shapiro-Wilk and Kolkogorov-Smirnov tests.