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

Abstract

Cutaneous leishmaniasis (CL) is caused byLeishmania 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 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.

A randomized double-blind Phase IIb trial to evaluate the efficacy of ChAd63-KH for the treatment of post kala-azar dermal leishmaniasis

“…Whilst evidence for such an immunoregulatory environment is less well established in PKDL and other forms of dermal leishmaniasis, some similarities to these other chronic diseases exist. For example, both IDO1 and PD-L1 are abundant in chronic cutaneous leishmaniasis lesions resulting from L. donovani infection in Sri Lanka, with a reduction in PD-L1 expression predicting rate of cure after antimonial chemotherapy 38 . More recently, we have identified expression of these checkpoint molecules in CL patients infected with L. ( V. ) braziliensis and also in PKDL patients infected with L. donovani in India 39 .…”

“…Whilst studies using existing biologics or other clinically approved drugs might provide proof of concept data in PKDL, it is recognised that such high-cost adjunct therapies are unlikely to drive vaccine implementation in a lower- and middle-income country (LMIC) setting. Alternatively, vaccination in conjunction with anti-leishmanial chemotherapy should also be considered, given previous successes with immunochemotherapy in PKDL 29 and more recent evidence suggesting that such chemotherapy may also diminish the immunoregulatory environment in CL patients 38 .…”

IL-32 producing CD8+memory T cells and Tregs define the IDO1 / PD-L1 niche in human cutaneous leishmaniasis skin lesions

“…Although differing mechanisms of immunopathology may occur across the leishmaniasis disease spectrum, IDO1 and PD-L1 have been consistently identified in transcriptomic studies 32,62,63,64,65 . To assess whether the CD274 and IDO1 niche composition we identified in SL_CL patients was also seen in other forms of dermal leishmaniasis, we performed Visium analysis on biopsies from four Brazilian patients with L. (V.) braziliensis CL (Fig.…”

Excretory/secretory proteins inhibit host immune responses by downregulating the TLR4/NF-κB/MAPKs signaling pathway: A possible mechanism of immune evasion in parasitic nematode Haemonchus contortus

“…LAG-3, PD-1, CTLA-4, and PD-L1 are suppressive immune checkpoints impair lymphocyte function (9,32,33). Similarly, the expression of these immune checkpoint molecules plays a vital role in the parasite's evasion of the host immune system (34)(35)(36)(37)(38). Therefore, in this study, the effect of HcESPs on the transcript levels of suppressive immune checkpoint molecules in PBMCs was assessed by qPCR assays.…”