Checkpoint blockade improves outcome in a mouse model of hepatic alveolar echinococcosis infection via maintenance of innate and adaptive immune balance

Abstract

Background: Alveolar echinococcosis is a severe zoonotic disease caused by Echinococcocus multilocularis infection that is in part dependent on local innate and adaptive immune responses. In this study the effect of PD-L1 and PD-1 inhibition on outcome of alveolar echinococcosis was tested in different mouse models. Methods: Wild type (WT) and PD-1 knock out (KO)mice were infected with EM and received anti-PD-L1 monoclonal antibody during one month. Lesions count and weight in the infected liver was measured at day 30 post infection. Immune responses were measured by assessing serum cytokines and intrahepatic and systemic immune responses by flow cytometry. Results: After oral as well as after intraperitoneal infection the extent of AE was significantly reduced after pharmacological inhibition or genetic deletion of PD-L1 or PD-1. Mechanistically, we observed in mice infected with AE reduction of protective cytokines such as IL-22 secretion by innate lymphoid cells. Adaptive immune cells such as CD4 and CD8 T cells are significantly elevated in response to infection. Injection of anti-PD-L1 restored the innate and adaptive immunity system balance with elevation of IL-22 secretion by group 1 innate lymphoid cells. Frequencies of CD4 and CD8 T cells decreased, while the frequency of CD4Treg increased after PD-1 blockade confirming its potential to maintain the immune balance. Conclusion: Inhibition of both, PD-1 and PD-L1 reduces the extent of AE infection via modulation of hepatic innate and adaptive immune cell responses. These findings reveal that the use of checkpoint inhibitors potentially may alter the clinical course of AE infection.