Immunotherapy of alveolar echinococcosis via PD‐1/PD‐L1 immune checkpoint blockade in mice

Abstract

Summary The growth potential of the tumour‐like Echinococcus multilocularis metacestode (causing alveolar echinococcosis, AE ) is directly dependent upon the nature/function of the periparasitic adaptive host immune‐mediated processes. PD ‐1/ PD ‐L1 pathway (programmed cell death 1), which inhibits lymphocytic proliferation in tumour development, is over‐expressed at the chronic stage of AE . We tested the impact of a PD ‐1/ PD ‐L1 pathway blockade on the outcome of both chronic AE (intraperitoneal metacestode inoculation, secondary AE and SAE ) and acute AE (peroral egg infection, primary AE and PAE ). To assess the parasite proliferation potential, we measured parasite mass weight for SAE and liver lesion number for PAE . In both models, the parasite load was significantly decreased in response to anti‐ PD ‐L1 antibody treatment. In SAE , anti‐ PDL 1 administration was associated with increased Th1 response parameters and decreased Treg responses, while in PAE anti‐ PDL 1 administration was associated with fewer lesions in the liver and decreased Treg/Th2 responses. Our findings highly suggested that a PD ‐1/ PD ‐L1 pathway blockade triggered the host immune responses in favour of an immune‐mediated control of E. multilocularis proliferation. Based on this, future studies that combine PD ‐1/ PD ‐L1 blockade with a parasitostatic albendazole medication may yield in a putatively curative therapeutic approach to control alveolar echinococcosis.

Immune Exhaustion of T Cells in Alveolar Echinococcosis Patients and Its Reversal by Blocking Checkpoint Receptor TIGIT in a Murine Model

“…Such observations are consistent with the effect of TIGIT on the generation of mature immunoregulatory dendritic cells; its role on the inhibition of TNF‐α secretion is also consistent with the dramatic effect of TNF gene deletion shown on E. multilocularis infection susceptibility in mice . Our results are also in line with observations that anti‐PD‐L1 mAb or recombinant EmP29 antigen administration result in a change of Treg and/or T h 2/T h 1 ratio, which may be responsible for partial restriction of metacestode growth . However, in most studies, positive results of immunotherapy were observed when the biotherapeutic agent was administered at time of infection, thus preventing the establishment of the metacestode, which is not applicable to the clinical situation.…”

“…Persistence of E. multilocularis is associated with a chronic granulomatous inflammation, leading to the disruption of the normal function of T cells, which is nowadays referred to as “functional exhaustion.” Recent reports have also shown that E. multilocularis infection is associated with the expression of “checkpoint” receptors that are known to limit the activity of parasite‐specific lymphocytes. We and others have shown that the receptors programmed cell‐death 1 (PDCD1), 2B4 (SLAMf4, CD244), and lymphocyte‐activation gene 3 (LAG3) are aberrantly expressed during chronic infection, and that they contribute to “exhausted” parasite‐induced T‐cell response and lead to the maintenance of E. multilocularis survival . Observations in humans and experimental studies in animals suggest that, in the absence of fully effective antiparasitic chemotherapy for AE, modulation of the host immune response, specifically, blocking the coinhibitory receptors (e.g., PDCD1), could be envisaged to fight against the parasite and to prevent the disease and/or its complications.…”

“…We and others have shown that the receptors programmed cell‐death 1 (PDCD1), 2B4 (SLAMf4, CD244), and lymphocyte‐activation gene 3 (LAG3) are aberrantly expressed during chronic infection, and that they contribute to “exhausted” parasite‐induced T‐cell response and lead to the maintenance of E. multilocularis survival . Observations in humans and experimental studies in animals suggest that, in the absence of fully effective antiparasitic chemotherapy for AE, modulation of the host immune response, specifically, blocking the coinhibitory receptors (e.g., PDCD1), could be envisaged to fight against the parasite and to prevent the disease and/or its complications. However, the checkpoint receptors expressed by T cells that actually play the most critical role in inducing functional exhaustion of anti ‐Echinococcus T cells remain poorly defined.…”

“…Blockade of the PDCD1–programmed death ligand 1 (PD‐L1) pathway during Leishmania donovani rescued L. donovani –specific CD8 + T cells from exhaustion with increased interferon (IFN)‐γ production and reduced splenic parasite burden . With regard to echinococcosis, up‐regulation of PDCD1 is associated with immunosuppression in the livers of mice, and PDCD1 blockade triggers the host immune responses to control E. multilocularis growth . Although anti‐CTLA4 and anti‐PDCD1/PD‐L1 blockades have already been proven successful in oncology and in preclinical studies in parasite infections, their benefit is limited to susceptible tumors or parasites and does not cover all situations .…”

“…(13) With regard to echinococcosis, up-regulation of PDCD1 is associated with immunosuppression in the livers of mice, and PDCD1 blockade triggers the host immune responses to control E. multilocularis growth. (8,9) Although anti-CTLA4 and anti-PDCD1/PD-L1 blockades have already been proven successful in oncology and in preclinical studies in parasite infections, their benefit is limited to susceptible tumors or parasites and does not cover all situations. (14) Looking for other checkpoint receptors has become necessary.…”