Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity

Zhang, Qing; Bi, Jiacheng; Zheng, Xiaodong; Chen, Yongyan; Wang, Hua; Wu, Wenyong; Wang, Zhengguang; Wu, Qiang; Peng, Hui; Wei, Haiming; Sun, Rui; Tian, Zhigang

doi:10.1038/s41590-018-0132-0

Cited by 752 publications

(703 citation statements)

References 36 publications

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“…TIGIT binds two ligands: the poliovirus receptor (CD155) and nectin‐2 (poliovirus receptor‐related 2; CD112) . Our recent results showed that TIGIT was a target for therapy in preclinical models, and its blockade antibody alone or in combination with anti‐PDCD1/PD‐L1 was successful in tumor immunotherapy . In the present study, we analyzed the TIGIT expression profile and functional roles in intrahepatic and peripheral T cells in both AE patients and in E. multilocularis –infected mice.…”

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confidence: 97%

“…The T‐cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine‐based inhibitory motif domain (TIGIT) is an inhibitory receptor expressed on effector T cells, memory T cells, regulatory T (Treg) cells, and natural killer (NK) cells and is involved in tumor or virus immunosurveillance . TIGIT binds two ligands: the poliovirus receptor (CD155) and nectin‐2 (poliovirus receptor‐related 2; CD112) .…”

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confidence: 99%

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

Zhang

Lin

et al. 2020

Hepatology

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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.

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confidence: 97%

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confidence: 99%

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

Zhang

Lin

et al. 2020

Hepatology

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“…High plasma IL‐10 levels and PD‐1 up‐regulation have been found associated to NK dysfunction in cancer patients, predicting poor prognosis . Recent work from Zhang and colleagues highlighted the role of the checkpoint receptor TIGIT in NK cell exhaustion in colon cancer and the re‐establishment of antitumor NK immunity by its blockade . CD96, TIGIT, and CD226 seem to be key players in the phenomenon and must be further investigated in the context of ALL .…”

Section: Discussionmentioning

confidence: 99%

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

Ramírez-Ramírez

Padilla-Castañeda

Galán-Enríquez

et al. 2019

Journal of Leukocyte Biology

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Due to their increasing rates of morbidity and mortality, childhood malignancies are considered a global health priority, with acute lymphoblastic leukemias (ALLs) showing the highest incidence worldwide. Control of malignant clone emergence and the subsequent normal‐leukemic hematopoietic cell out‐competition require antitumor monitoring mechanisms. Investigation of cancer surveillance innate cells may be critical to understand the mechanisms contributing in either disease progression or relapse, and to promote displacement of leukemic hematopoiesis by the normal counterpart. We report here that NK cell production is less and low hematopoietic progenitor numbers contribute to this defect. By investigating the expression of the activation molecule class I restricted T‐cell associated molecule (CRTAM) along the hematopoietic lineage differentiation pathway, we have identified lymphoid precursor populations coexpressing CD34, CD56/CD3/CD19, and CRTAM as the earliest developmental stage where activation may take place in specialized niches that display the ligand nectin‐like‐2. Of note, bone marrow (BM) from patients with ALL revealed high contents of preactivated CD56high NK cells expressing CRTAM and endowed with an exhaustion‐like phenotype and the functional capability of producing IL‐10 and TGF‐β in vitro. Our findings suggest, for the first time, that the tumor microenvironment in ALL directly contribute to exhaustion of NK cell functions by the CRTAM/Necl‐2 interaction, and that the potential regulatory role of exhausted‐like NK cells may favor malignant progression at the expense of anti‐tumor responses. Phenotypic and functional identity of this unique suppressor‐like NK cell population within the leukemic BM would be of special interest for the pathobiology of ALL and development of targeting strategies.

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“…Recent data has demonstrated that the blocking of TIGIT interaction by means of genetic ablation or by using anti‐TIGIT mAb's led to enhanced NK cell antitumor immunity. Consequently, improvement in the control of tumor growth in a mouse model of metastasis was observed . Accordingly, antimetastatic activity following CD96 blocking was shown in 3 preclinical tumor models .…”

Section: Nk Cell Receptorsmentioning

confidence: 99%

From the “missing self” hypothesis to adaptive NK cells: Insights of NK cell-mediated effector functions in immune surveillance

Cruz-Muñoz

Valenzuela-Vázquez

Sánchez-Herrera

et al. 2019

Journal of Leukocyte Biology

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The original discovery of NK cells approximately 40 yr ago was based on their unique capability to kill tumor cells without prior sensitization or priming, a process named natural cytotoxicity. Since then, several studies have documented that NK cells can kill hematopoietic and nonhematopoietic cancer cells. NK cells also recognize and kill cells that have undergone viral infections. Besides natural cytotoxicity, NK cells are also major effectors of antibody‐dependent cell cytotoxicity (ADCC). Therefore, NK cells are well “armed” to recognize and mount immune responses against “insults” that result from cell transformation and viral infections. Because of these attributes, an essential role of NK cells in tumor surveillance was noted. Indeed, several studies have shown a correlation between impaired NK cell cytotoxicity and a higher risk of developing cancer. This evidence led to the idea that cancer initiation and progress is intimately related to an abnormal or misdirected immune response. Whereas all these ideas remain current, it is also true that NK cells represent a heterogeneous population with different abilities to secrete cytokines and to mediate cytotoxic functions. In addition, recent data has shown that NK cells are prone to suffer epigenetic modifications resulting in the acquisition of previously unrecognized attributes such as memory and long‐term survival. Such NK cells, referred as “adaptive” or “memory‐like,” also display effector functions that are not necessarily equal to those observed in conventional NK cells. Given the new evidence available, it is essential to discuss the conceptual reasoning and misconceptions regarding the role of NK cells in immune surveillance and immunotherapy.

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Blockade of the checkpoint receptor TIGIT prevents NK cell exhaustion and elicits potent anti-tumor immunity

Cited by 752 publications

References 36 publications

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

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

CRTAM+ NK cells endowed with suppressor properties arise in leukemic bone marrow

From the “missing self” hypothesis to adaptive NK cells: Insights of NK cell-mediated effector functions in immune surveillance

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