Auteurs:
Fadi Jebbawi (Bern | CH)
Anne-Pauline Bellanger (Besancon | FR)
Britta Lundström-Stadelmann (Bern | CH)
Reto Rufener (Bern | CH)
Michel Dosch (Bern | CH)
Guido Beldi (Bern | CH)
Laurence Millon (Besancon | CH)
Bruno Gottstein (Bern | CH)
Junhua Wang (Bern | CH)
PD-1/PD-L1 immune checkpoint blockade has shown to be efficient in cancer therapy, by modulating immune cell responses in favor of the host thus inducing immunological memory and limiting tissue pathology. One of our previous study showed that PD-1/PD-L1 was also effective against both primary and secondary E. multilocularis infection (alveolar echinococcosis, AE) by regulating T cell immunity. This ensuing study tackles the potential to combine PD-1/PD-L1 blockade with conventional albandazole (ABZ) medication in experimental murine AE. Treatment was started at 6 weeks post E. multilocularis infection, and maintained for 8 weeks with twice/week anti-PD-L1 intraperitoneally, or 5 days/week ABZ perorally, or BOTH combined. As key parameters we assessed parasite weight, immune cell profile, tissue histology, and liver tissue cytokine levels. Findings showed that E. multilocularis infection alone led to the formation of an excess in inflammatory cytokines, Treg cells, and a decrease in Kupffer cells, in neutrophils and in high cytotoxicity upon NK and NKT cells. Combined therapy showed the highest effect against the parasite (lowest parasite mass recovered), while ABZ alone already increased the inflammatory immune response, and PD-L1 blockade alone increased T cell immune responses (mainly via Tregs) but with decreased inflammation and cytotoxic NK and NKT cells. Moreover, PD-L1 blockade increased numbers of Kupffer cells and neutrophils infiltrating the liver. This study suggests that the PD-1/PD-L1 pathway plays an important role by regulating adaptive and innate immune cells against E. multilocularis infection, without causing significant tissue damage.
Based on this, future studies will have to be designed, aiming at clinical trials with PD-1/PD-L1 blockade in human AE patients, which may yield into an alternative therapeutic approach to control AE especially in those patients who do not respond well to ABZ, or this approach may even putatively provide a curative therapeutical outcome in all AE patients receiving a combined PD-1/PD-L1 blockade and ABZ medication.