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

TY - JOUR

T1 - Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis

AU - Dey, Nidhi S

AU - Senaratne, Sujai

AU - Somaratne, Vijani

AU - Madarasinghe, Nayani P

AU - Seneviratne, Bimalka

AU - Forrester, Sarah

AU - Montes de Oca, Marcela

AU - Reis, Luiza Campos

AU - Moulik, Srija

AU - Walrad, Pegine B

AU - Chatterjee, Mitali

AU - Goto, Hiro

AU - Wickremasinghe, Renu

AU - Lagos, Dimitris

AU - Kaye, Paul M

AU - Ranasinghe, Shalindra

N1 - © 2021, Dey et al.

PY - 2021/10/5

Y1 - 2021/10/5

N2 - 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.

AB - 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.

U2 - 10.1172/JCI142765

DO - 10.1172/JCI142765

M3 - Article

C2 - 34609968

SN - 0021-9738

VL - 131

JO - Journal of Clinical Investigation

JF - Journal of Clinical Investigation

IS - 22

M1 - e142765

ER -