Higher TIGIT<sup>+</sup>CD226<sup>-</sup> γδ T cells in Patients with Acute Myeloid Leukemia

Jin, Zhenyi; Lan, Tianbi; Zhao, Yun; Jin-xia, DU; Chen, Jie; Lai, Jing; Xu, Ling; Chen, Shaohua; Zhong, Xueyun; Wu, Xiuli; Li, Yangqiu

doi:10.1080/08820139.2020.1806868

Cited by 35 publications

(25 citation statements)

References 43 publications

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“…Similarly, TIGIT expression was observed on CD57+ NK cells in CML which might be a reason of NK cell dysfunction in CML [ 93 ]. Similar results were obtained in studies on TIGIT in AML [ 94 , 95 ]. Contrary to previous findings, Stamm et al reported that TIGIT ligands - CD155 and CD112 are highly expressed on AML cells and blockade of TIGIT-CD155/CD112 axis significantly increased lysis of leukemic cells in vitro in a culture with healthy whole PBMCs (peripheral blood mononuclear cells) [ 96 ].…”

Section: Leukemia-derived Factors That Promote Immune Evasionsupporting

confidence: 89%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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Both chronic myeloid leukemia and acute myeloid leukemia evade the immune response during their development and disease progression. As myeloid leukemia cells modify their bone marrow microenvironment, they lead to dysfunction of cytotoxic cells, such as CD8+ T cells or NK cells, simultaneously promoting development of immunosuppressive regulatory T cells and suppressive myeloid cells. This facilitates disease progression, spreading of leukemic blasts outside the bone marrow niche and therapy resistance. The following review focuses on main immunosuppressive features of myeloid leukemias. Firstly, factors derived directly from leukemic cells – inhibitory receptors, soluble factors and extracellular vesicles, are described. Further, we outline function, properties and origin of main immunosuppressive cells - regulatory T cells, myeloid derived suppressor cells and macrophages. Finally, we analyze interplay between recovery of effector immunity and therapeutic modalities, such as tyrosine kinase inhibitors and chemotherapy.

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Section: Leukemia-derived Factors That Promote Immune Evasionsupporting

confidence: 89%

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Swatler

Turos-Korgul

Kozłowska

et al. 2021

Cancers

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“…In addition to PD1/PD-L1, other inhibitory proteins are highly regulated in LCs (i.e., CTLA4, BTLA, TIGIT, TIM3 and LAG3) and their effects on gd T cells have not yet been fully investigated (26,159,(214)(215)(216). However, previous studies have shown that some of these receptors have great potential for deregulating their antitumor activity, reflecting in cytokine production (213,217).…”

Section: Blocking Immune Checkpoints In Gd T Cells and Leukemic Cellsmentioning

confidence: 99%

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

et al. 2021

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Recently, many discoveries have elucidated the cellular and molecular diversity in the leukemic microenvironment and improved our knowledge regarding their complex nature. This has allowed the development of new therapeutic strategies against leukemia. Advances in biotechnology and the current understanding of T cell-engineering have led to new approaches in this fight, thus improving cell-mediated immune response against cancer. However, most of the investigations focus only on conventional cytotoxic cells, while ignoring the potential of unconventional T cells that until now have been little studied. γδ T cells are a unique lymphocyte subpopulation that has an extensive repertoire of tumor sensing and may have new immunotherapeutic applications in a wide range of tumors. The ability to respond regardless of human leukocyte antigen (HLA) expression, the secretion of antitumor mediators and high functional plasticity are hallmarks of γδ T cells, and are ones that make them a promising alternative in the field of cell therapy. Despite this situation, in particular cases, the leukemic microenvironment can adopt strategies to circumvent the antitumor response of these lymphocytes, causing their exhaustion or polarization to a tumor-promoting phenotype. Intervening in this crosstalk can improve their capabilities and clinical applications and can make them key components in new therapeutic antileukemic approaches. In this review, we highlight several characteristics of γδ T cells and their interactions in leukemia. Furthermore, we explore strategies for maximizing their antitumor functions, aiming to illustrate the findings destined for a better mobilization of γδ T cells against the tumor. Finally, we outline our perspectives on their therapeutic applicability and indicate outstanding issues for future basic and clinical leukemia research, in the hope of contributing to the advancement of studies on γδ T cells in cancer immunotherapy.

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“…The association of DNAM-1/TIGIT, another immune checkpoint, with immune evasion has been mainly reported in T cells ( 37 ). In addition to the presence of high frequencies of CD8 + T cells expressing TIGIT in patients with FLT3 -ITD mutations, a decrease in CD226 + γδ T cells and an increase in TIGIT + γδ T cells in patients with de novo AML have been reported ( 38 ). It has also been reported that TIGIT − DNAM-1 + γδ T cells are restored in patients with AML who achieve complete remission after chemotherapy.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been reported that TIGIT − DNAM-1 + γδ T cells are restored in patients with AML who achieve complete remission after chemotherapy. Furthermore, the high expression of TIGIT + DNAM-1 − in γδ T cells may be a biomarker of poor OS ( 38 ).…”

Section: Discussionmentioning

confidence: 99%

CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia

et al. 2021

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Acute myeloid leukemia (AML) relapse is considered to be related to escape from antitumor immunity. Changes in the expression of immune checkpoints, including B7 homolog (H)1 and B7-H2, have been reported to contribute to AML progression. Binding of T cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domain (TIGIT) among other immune checkpoints on natural killer (NK) and T cells to CD155/CD112 in tumors is supposed to be inhibitory; however, the mechanism by which changes in CD155 and CD112 expression affect tumor immunity remains unclear. When the increased expression of CD155 and CD112 activates Raf-MEK-ERK pathway and Raf-MEK-ERK pathway is one of the targets of FMS-like tyrosine kinase 3 ( FLT3 ) inhibition. The present study investigated the alterations in CD155 and CD112 expression under FLT3 inhibition (quizartinib and gilteritinib) and studied its effect on NK and T cell cytotoxicity. CD155 and CD112 expression was analyzed using flow cytometry and reverse transcription-quantitative PCR in AML cell lines with or without FLT3 mutation using FLT3 inhibitors. CD155 and CD112 expression was specifically downregulated by FLT3 inhibition in FLT3 -mutated cell lines. Direct cytotoxicity and antibody-dependent cellular cytotoxicity against these cells by NK cells were enhanced. However, the cytotoxicity of γδ T cells with low TIGIT expression compared with NK cells was not enhanced in direct cytotoxicity assay using luciferase luminescence. The analysis of clinical trials from The Cancer Genome Atlas (TCGA) revealed that high CD155 and CD112 expression is associated with poor overall survival. The enhanced cytotoxicity of NK cells against CD155- and CD112-downregulated cells following FLT3 inhibition indicated CD155 and CD112 as possible targets of immunotherapy for AML using FLT3 inhibitors.

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Higher TIGIT⁺CD226^- γδ T cells in Patients with Acute Myeloid Leukemia

Cited by 35 publications

References 43 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia

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Higher TIGIT+CD226- γδ T cells in Patients with Acute Myeloid Leukemia

Cited by 35 publications

References 43 publications

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

Immunosuppressive Cell Subsets and Factors in Myeloid Leukemias

γδ T Cells for Leukemia Immunotherapy: New and Expanding Trends

CD155 and CD112 as possible therapeutic targets of FLT3 inhibitors for acute myeloid leukemia

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Higher TIGIT⁺CD226^- γδ T cells in Patients with Acute Myeloid Leukemia