Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis.
Early reduction in PD-L1 expression predicts faster treatment response in human cutaneous leishmaniasis.
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DOI：
10.1172/jci142765
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发表时间：
2021-11-15
期刊：
影响因子：
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通讯作者：
Ranasinghe S
中科院分区：
文献类型：
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作者：
Dey NS;Senaratne S;Somaratne V;Madarasinghe NP;Seneviratne B;Forrester S;Montes de Oca M;Reis LC;Moulik S;Walrad PB;Chatterjee M;Goto H;Wickremasinghe R;Lagos D;Kaye PM;Ranasinghe S
皮肤利什曼病（CL）是由杜氏利什曼原虫在斯里兰卡引起的。五价锑（例如，葡萄糖酸锑钠[SSG]）仍然是CL一线药物，没有新的有效治疗方法出现。我们研究了斯里兰卡CL患者在就诊时和SSG治疗期间的全血和病变转录组。从病变而不是全血中，我们确定了治疗开始后免疫相关基因（包括免疫检查点分子）的差异表达。使用空间分析和RNA-FISH，我们证实了在第二个验证队列的病变中治疗时程序性死亡配体1（PD-L1）和吲哚胺2，3-双加氧酶1（IDO 1）蛋白的表达减少，并进一步证明了与未感染的病变CD 68+单核细胞和巨噬细胞相比，寄生虫感染的这些检查点分子的表达显著更高。至关重要的是，PD-L1而不是IDO 1表达的早期降低可预测临床治愈率（HR = 4.88），并且与寄生虫负荷的降低平行发生。我们的数据支持一种模型，即锑类药物的初始抗利什曼原虫活性增强了对T细胞的检查点抑制，促进了免疫-药物协同作用和临床治愈。我们的研究结果表明，PD-L1表达可用作斯里兰卡SSG治疗临床反应快速性的预测因子，并支持进一步评估PD-L1作为利什曼病的宿主导向治疗剂。
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.