TIGIT-CD226-PVR axis: advancing immune checkpoint blockade for cancer immunotherapy

Journal for ImmunoTherapy of Cancer, Journal Year: 2022, Volume and Issue: 10(4), P. e004711 - e004711

Published: April 1, 2022

Recent advances in understanding the roles of immune checkpoints allowing tumors to circumvent system have led successful therapeutic strategies that fundamentally changed oncology practice. Thus far, immunotherapies against only two checkpoint targets been approved, CTLA-4 and PD-L1/PD-1. Antibody blockade these enhances function antitumor T cells at least part by relieving inhibition cell costimulatory receptor CD28. These successes stimulated considerable interest identifying other pathways may bte targeted alone or together with existing immunotherapies. One such axis is comprised members PVR/nectin family includes inhibitory immunoreceptor Ig tyrosine-based domains (TIGIT). Interestingly, TIGIT acts regulate activity a second CD226 works parallel There are currently over dozen TIGIT-directed blocking antibodies various phases clinical development, testament promise modulating this pathway enhance responses. In review, we discuss role as inhibitor, its interplay activating counter-receptor CD226, status next advance cancer immunotherapy.

Language: Английский

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NK cells and solid tumors: therapeutic potential and persisting obstacles

Molecular Cancer, Journal Year: 2022, Volume and Issue: 21(1)

Published: Nov. 1, 2022

Abstract Natural killer (NK) cells, which are innate lymphocytes endowed with potent cytotoxic activity, have recently attracted attention as potential anticancer therapeutics. While NK cells mediate encouraging responses in patients leukemia, the therapeutic effects of cell infusion solid tumors limited. Preclinical and clinical data suggest that efficacy against malignancies is hampered by several factors including inadequate tumor infiltration persistence/activation microenvironment (TME). A number metabolic features TME hypoxia well elevated levels adenosine, reactive oxygen species, prostaglandins negatively affect activity. Moreover, cancer-associated fibroblasts, tumor-associated macrophages, myeloid-derived suppressor regulatory T actively suppress cell-dependent immunity. Here, we review cellular barriers inhibit neoplasms discuss strategies to circumvent such obstacles towards superior

Language: Английский

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Co-inhibition of TIGIT and PD-1/PD-L1 in Cancer Immunotherapy: Mechanisms and Clinical Trials

Molecular Cancer, Journal Year: 2023, Volume and Issue: 22(1)

Published: June 8, 2023

Abstract Over the past decade, immune checkpoint inhibitors (ICIs) have emerged as a revolutionary cancer treatment modality, offering long-lasting responses and survival benefits for substantial number of patients. However, response rates to ICIs vary significantly among individuals types, with notable proportion patients exhibiting resistance or showing no response. Therefore, dual ICI combination therapy has been proposed potential strategy address these challenges. One targets is TIGIT, an inhibitory receptor associated T-cell exhaustion. TIGIT diverse immunosuppressive effects on immunity cycle, including inhibition natural killer cell effector function, suppression dendritic maturation, promotion macrophage polarization M2 phenotype, differentiation T cells regulatory cells. Furthermore, linked PD-1 expression, it can synergize PD-1/PD-L1 blockade enhance tumor rejection. Preclinical studies demonstrated co-inhibition in enhancing anti-tumor improving outcomes several types. Several clinical trials are underway evaluate safety efficacy various results awaited. This review provides overview mechanisms treatment, summarizes latest investigating this therapy, discusses its prospects. Overall, represents promising therapeutic approach that improve treated ICIs.

Language: Английский

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Targeting PD-1/PD-L1 pathway in myelodysplastic syndromes and acute myeloid leukemia

Experimental Hematology and Oncology, Journal Year: 2022, Volume and Issue: 11(1)

Published: March 2, 2022

Myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) are clonal hematopoietic stem cell diseases arising from the bone marrow (BM), approximately 30% of MDS eventually progress to AML, associated with increasingly aggressive neoplastic clones poor survival. Dysregulated immune microenvironment has been recognized as a key pathogenic driver causing high rate intramedullary apoptosis in lower-risk immunosuppression higher-risk AML. Immune checkpoint molecules, including programmed death-1 (PD-1) death ligand-1 (PD-L1), play important roles oncogenesis by maintaining an immunosuppressive tumor microenvironment. Recently, both molecules have examined Abnormal inflammatory signaling, genetic and/or epigenetic alterations, interactions between cells, treatment patients all involved dysregulating PD-1/PD-L1 signaling these two diseases. Furthermore, pathway activated microenvironment, milieu BM shift immunosuppressive, contributing evolution blasts. Nevertheless, numerous preclinical studies suggested potential response blocker. Current clinical trials employing drugs AML reported mixed responses. In this paper, we focus on recent advances available ongoing outcomes inhibitor patients. We also discuss novel blocker-based immunotherapeutic strategies challenges, identifying reliable biomarkers, determining settings, exploring optimal combination therapies.

Language: Английский

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Targeting the innate immune system in pediatric and adult AML

Leukemia, Journal Year: 2024, Volume and Issue: 38(6), P. 1191 - 1201

Published: March 8, 2024

Abstract While the introduction of T cell-based immunotherapies has improved outcomes in many cancer types, development for both adult and pediatric AML been relatively slow limited. In addition to need identify suitable target antigens, a better understanding immunosuppressive tumor microenvironment is necessary design novel immunotherapy approaches. To date, most immune characterization studies have focused on cells, while innate lineages such as monocytes, granulocytes natural killer (NK) received less attention. solid cancers, shown that macrophages, myeloid-derived suppressor cells neutrophils are highly plastic may differentiate into depending signals their microenvironment, NK appear be functionally impaired. Hence, an in-depth compartment TME urgently needed guide immunotherapeutic interventions AML. this review, we summarize current knowledge AML, discuss how targeting its components enhance cell-based- other

Language: Английский

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Targeting natural killer cells: from basic biology to clinical application in hematologic malignancies

Experimental Hematology and Oncology, Journal Year: 2024, Volume and Issue: 13(1)

Published: Feb. 23, 2024

Natural killer (NK) cell belongs to innate lymphoid family that contributes host immunosurveillance and defense without pre-immunization. Emerging studies have sought understand the underlying mechanism behind NK dysfunction in tumor environments, provide numerous novel therapeutic targets for treatment. Strategies enhance functional activities of exhibited promising efficacy favorable tolerance clinical treatment patients, such as immune checkpoint blockade (ICB), chimeric antigen receptor (CAR-NK) cell, bi/trispecific engager (BiKE/TriKE). Immunotherapy targeting provides remarkable advantages compared T therapy, including a decreased rate graft versus-host disease (GvHD) neurotoxicity. Nevertheless, advanced details on how support maintenance function obtain better response longer duration still remain be elucidated. This review systematically summarizes profound role cells development, highlights up-to-date advances current challenges therapy hematologic malignancies.

Language: Английский

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Increased TIGIT expression correlates with impaired NK cell function in diffuse large B-cell lymphoma

Frontiers in Oncology, Journal Year: 2025, Volume and Issue: 15

Published: March 31, 2025

This study aims to investigate the status of natural killer (NK) cells and role T-cell immunoreceptor with Ig ITIM domains (TIGIT)-mediated regulation in diffuse large B-cell lymphoma (DLBCL). Peripheral blood samples from 30 newly diagnosed DLBCL patients 25 healthy controls were collected. Multiparametric flow cytometry was used analyze expression levels TIGIT its family molecules (CD226 CD96) on NK cells, as well assess cell phenotype function. The restorative effects blockade cytotoxicity evaluated through vitro functional assays vivo animal models. Compared controls, exhibited significantly reduced percentages absolute numbers cells. markedly upregulated patients, while CD226 downregulated; however, no significant difference CD96 observed. These alterations associated impaired function including secretion activation factors such granzyme B, perforin, CD107a. Importantly, enhanced cytotoxic activity against both settings. Dysregulated contributes dysfunction promotes tumor immune escape DLBCL. findings highlight a promising therapeutic target for restoring cell-mediated antitumor immunity

Language: Английский

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Combined Blockade of TIGIT and CD39 or A2AR Enhances NK-92 Cell-Mediated Cytotoxicity in AML

International Journal of Molecular Sciences, Journal Year: 2021, Volume and Issue: 22(23), P. 12919 - 12919

Published: Nov. 29, 2021

This study aimed to characterize different natural killer (NK) cell phenotypes on bone marrow and peripheral blood cells from acute myeloid leukemia (AML) patients healthy donors (HDs). Our data show that CD56dimCD16- CD56brightCD16- NK represent the predominant subpopulations in AML, while CD56dimCD16+ are significantly reduced compared HDs. Moreover, TIGIT+ PVRIG+ cluster subset whereas CD39+ CD38+ do so AML. Furthermore, functional effects of (co-)blockade TIGIT CD39 or A2AR functionality were analyzed. These experiments revealed single blockade receptor results an increased NK-92 cell-mediated killing AML vitro. Combined targeting augments anti-TIGIT-mediated lysis cells. indicate distinct subsets exhibit immunosuppressive patterns (via TIGIT/PVRIG receptors purinergic pathway). In summary, we conclude TIGIT, CD39, constitute relevant inhibitory checkpoints patients. A combinatorial synergistically strengthens cytotoxicity. As inhibitors clinically available, studies their combined use could be conducted near future.

Language: Английский

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TIGIT Expression on Activated NK Cells Correlates with Greater Anti-Tumor Activity but Promotes Functional Decline upon Lung Cancer Exposure: Implications for Adoptive Cell Therapy and TIGIT-Targeted Therapies

Cancers, Journal Year: 2023, Volume and Issue: 15(10), P. 2712 - 2712

Published: May 11, 2023

Treatments targeting TIGIT have gained a lot of attention due to strong preclinical and early clinical results, particularly with anti-PD-(L)1 therapeutics. However, this combination has failed meet progression-free survival endpoints in phase III trials. Most our understanding comes from studies T cell function. Yet, inhibitory receptor is often upregulated the same, or higher, extent on NK cells cancers. Studies murine models demonstrated that inhibits promotes exhaustion, its effects tumor control also being dependent cells. there are limited assessing role function human (hNK), lung cancer. used lines tested blockade reactivate exhausted obtained cancer patients. For therapeutic advancement, better context activated hNK crucial, which different than cells, critical adoptive therapeutics may be combined blockade. In study, effect anti-tumor activities ex vivo-expanded was evaluated vitro expression higher and/or expanded compared resting More

Language: Английский

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The role of exhausted natural killer cells in the immunopathogenesis and treatment of leukemia

Cell Communication and Signaling, Journal Year: 2024, Volume and Issue: 22(1)

Published: Jan. 22, 2024

Abstract The immune responses to cancer cells involve both innate and acquired cells. In the meantime, most attention has been drawn adaptive cells, especially T while, it is now well known that natural killer (NK) play a vital role in defending against malignancies. While are trying eliminate malignant try prevent function of these suppress responses. suppression NK various cancers can lead induction an exhausted phenotype which will impair their function. Recent studies have shown occurrence this types leukemic malignancies affect prognosis disease, targeting may be considered new immunotherapy method treatment leukemia. Therefore, detailed study diseases help understand mechanisms leukemia progression design methods by creating deeper understanding Here, we comprehensively review immunobiology

Language: Английский

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