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

Abstract

Background and Aims The cestode Echinococcus multilocularis infection, a serious health problem worldwide, causes alveolar echinococcosis (AE), a tumor‐like disease predominantly located in the liver and able to spread to any organs. Until now, there have been few studies that explore how T‐cell exhaustion contributes to the parasite’s escape from immune attack and how it might be reversed. Approach and Results In this study, we found that liver T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT) expression was significantly enhanced and positively correlated with lesion activity in AE patients. High TIGIT expression in both liver‐infiltrating and blood T cells was associated with their functional exhaustion, and its ligand CD155 was highly expressed by hepatocytes surrounding the infiltrating lymphocytes. In co‐culture experiments using human blood T cells and hepatic cell line HL‐7702, CD155 induced functional impairment of TIGIT+ T cells, and in vitro blockade with TIGIT antibody restored the function of AE patients’ T cells. Similar TIGIT‐related functional exhaustion of hepatic T cells and an abundant CD155 expression on hepatocytes were observed in E. multilocularis–infected mice. Importantly, in vivo blocking TIGIT prevented T‐cell exhaustion and inhibited disease progression in E. multilocularis–infected mice. Mechanistically, CD4+ T cells were totally and CD8+ T cells partially required for anti‐TIGIT–induced regression of parasite growth in mice. Conclusions This study demonstrates that E. multilocularis can induce T‐cell exhaustion through inhibitory receptor TIGIT, and that blocking this checkpoint may reverse the functional impairment of T cells and represent a possible approach to immunotherapy against AE.

Echinococcus multilocularis vesicular fluid induces the expression of immune checkpoint proteins in vitro

“…Over the past decades, studies performed in mice models and in patients demonstrated that the persistence of the larval E. multilocularis infection led to immune tolerance, which is mediated by T‐cell exhaustion 18 . Arguments concur to support a mechanistic hypothesis that several inhibitory immune checkpoints involved in lymphocytic proliferation are upregulated during alveolar echinococcosis: the previous publications demonstrating the role of the PD‐1/PD‐L1 pathway, 9,10 recent Chinese studies showing increased expression of LAG‐3 and of TIGIT in T cells of mice infected with E. multilocularis 19,20 as well as the present in vitro results.…”

Quantitative evaluation of range and metabolic activity of hepatic alveolar echinococcosis lesion microenvironment using PET/CT and multi-site sampling method

“…Besides, sample acquisition from LME liver and adjacent liver tissues (respectively for experimental and control groups) has been introduced to study immunology, brosis, pathophysiological changes etc. of the host [5][6][7][8]. However, there was no clear evidence for such sampling method that could clearly differentiate the real experimental and control liver tissues by separating the immune cell in ltrative boundary.…”

“…In this prospective study, we collected surgical hepatic AE subjects' preoperative computed tomography (CT), PET/CT, clinical data, and LME liver samples acquired through multi-site sampling method (MSS). Our primary research results concerning such sampling method for immunological study has been reported as "at least 2 cm distant from lesion" as a method to obtain adjacent normal liver tissue for controls previously [5]. Currently, we nished this prospective study that mainly focused on TBRs' differences and quanti cation of LME ranges in several lesion categories.…”

Quantitative evaluation of range and metabolic activity of hepatic alveolar echinococcosis lesion microenvironment using PET/CT and multi-site sampling method

“…Besides, sample acquisition from LME liver and adjacent liver tissues (respectively for experimental and control groups) has been introduced to study immunology, fibrosis, pathophysiological changes etc. of the host [5][6][7][8]. However, there was no clear evidence for such sampling method that could clearly differentiate the real experimental and control liver tissues by separating the immune cell infiltrative boundary.…”

“…In this prospective study, we collected surgical hepatic AE subjects' preoperative computed tomography (CT), PET/CT, clinical data, and LME liver samples acquired through multi-site sampling method (MSS). Our primary research results concerning such sampling method for immunological study has been reported as "at least 2 cm distant from lesion" as a method to obtain adjacent normal liver tissue for controls previously [5]. Currently, we finished this prospective study that mainly focused on TBRs' differences and quantification of LME ranges in several lesion categories.…”