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 4

Clinical correlates of PD-L1 reduction on treatment in patients with CL.

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Clinical correlates of PD-L1 reduction on treatment in patients with CL....
(A) Patients (validation cohort; n = 23) were stratified based on high (> geomean value; n = 11) and low (< geomean value; n = 12) pre-/on-treatment expression ratio. (B) Kaplan-Meier curve based on pre-/on-treatment ratio of PD-L1 expression (high versus low). (C) Patients stratified based on on-treatment expression of PD-L1 (> geomean value; n = 11 versus < geomean value; n = 12). (D) Multivariate Cox proportional hazards model plotted as a forest plot. P values for each covariate represent Wald statistic value, and overall statistical significance is also indicated. (E) Patients stratified by LITS1 PCR status (n = 9 PCR+ versus n = 14 PCR– or PCR+/– [equivocal]) on treatment. (F) PD-L1 expression in LITS PCR+ versus PCR– individuals on treatment. Dotted lines show upper and lower quantile, solid line shows median. P value generated using 2-tailed Mann-Whitney test. Vertical line drawn in B, C, and E on the x axis shows time when on-treatment biopsies were collected. Curves in B, C, and E were compared using log-rank (Mantel-Cox) test. Blue and red shaded areas show 95% CI of the 2 groups.