Increased TIGIT expressing NK cells with dysfunctional phenotype in AML patients correlated with poor prognosis

Liu, Guanfang; Zhang, Qi; Yang, Jingying; Li, Xiaomin; Xian, Luhua; Li, Wenmin; Lin, Tzu Chen; Cheng, Juan; Lin, Qiwen; Xu, Xiuzhang; Qin, Li; Lin, Yan‐Hui; Zhou, Mi; Shen, Erxia

doi:10.1007/s00262-021-02978-5

Cited by 42 publications

(37 citation statements)

References 42 publications

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“…Additionally, NK cell-mediated lysis of leukemias was dependent on CD226 [ 47 ]. Liu et al also recently illustrated that TIGIT + NK cells exhibit lower anti-leukemia effects, manifested by reduced cytokine production, degranulation, and cytotoxicity [ 17 ]. We confirmed these effects and extended their observations, showing that TIGIT blockade in combination with targeting the purinergic signaling could further enhance the anti-leukemic function of NK cells [ 17 ].…”

Section: Discussionmentioning

confidence: 99%

“…Liu et al also recently illustrated that TIGIT + NK cells exhibit lower anti-leukemia effects, manifested by reduced cytokine production, degranulation, and cytotoxicity [ 17 ]. We confirmed these effects and extended their observations, showing that TIGIT blockade in combination with targeting the purinergic signaling could further enhance the anti-leukemic function of NK cells [ 17 ]. Our results are also in line with data from solid cancer, where blockade of TIGIT could boost functional responsiveness of NK cell subsets against ovarian cancer cell lines [ 48 ].…”

Section: Discussionmentioning

confidence: 99%

“…Besides KIRs, NK cells can express further multiple inhibitory receptors, such as CD94/NKG2A, hepatitis A virus cellular receptor (TIM-3), and the T cell immunoreceptor with Ig and ITIM domains (TIGIT) [ 1 , 16 ]. Even if their functional potential has been much less studied compared to that in T cells [ 3 ], in acute myeloid leukemia (AML), it was recently found that a higher frequency of TIGIT + NK cells in the blood was associated with a poorer prognosis [ 17 ]. TIGIT and the poliovirus receptor-related immunoglobulin domain-containing protein (PVRIG, CD112R) are inhibitory receptors that compete with DNAX accessory molecule-1 (DNAM-1, CD226), an activating receptor that is downregulated on NK cells in AML [ 18 ], for their ligands poliovirus receptor (PVR, CD155) and poliovirus receptor-related 2 (PVRL2, CD112).…”

Section: Introductionmentioning

confidence: 99%

“…There are additional functional advantages of employing NK cells in contrast to T cells [ 33 ]. In AML, impaired NK cell function was associated with AML progress [ 17 , 34 ]. One of the advantages of developing allogeneic ready-to-use chimeric antigen receptor (CAR)-NK cells compared with CAR-T cells is their greater safety [ 35 , 36 ] because of their independence of HLA matching [ 13 ].…”

Section: Introductionmentioning

confidence: 99%

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

Brauneck

Seubert

Wellbrock

et al. 2021

IJMS

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

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

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

Brauneck

Seubert

Wellbrock

et al. 2021

IJMS

View full text Add to dashboard Cite

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“…TIGIT expression appears to be associated with an advanced disease status and poor clinical outcomes in several cancers [16][17][18]. A previous meta-analysis of cancers demonstrated that a high TIGIT expression is correlated with worse OS and PFS [19], and in hematological malignancies, high TIGIT expression is associated with poor clinical outcomes in patients with follicular lymphoma [20] and AML [21,22]. In a previous study on MM, TIGIT expression was upregulated in CD8 + T cells during myeloma progression and associated with impaired effector functions [23].…”

Section: Introductionmentioning

confidence: 99%

PVR (CD155) Expression as a Potential Prognostic Marker in Multiple Myeloma

Lee

Kim

Kang

et al. 2022

Preprint

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Poliovirus receptor (PVR, CD155) is upregulated during tumor progression, and PVR expression is associated with poor prognosis in patients with cancer; however, prognostic implications for PVR in multiple myeloma (MM) have not been investigated. We assessed PVR expression in bone marrow samples of 125 patients via immunohistochemistry (IHC) and in those of 22 patients via enzyme-linked immunosorbent assay (ELISA) and quantitative polymerase chain reaction. Additionally, we evaluated TIGIT levels in bone marrow CD8+ T cells and natural killer cells in 14 patients using flow cytometry. Soluble PVR and TIGIT levels in 22 patients were measured using ELISA. PVR clinical and prognostic significance were assessed using a histoscore via IHC. PVR was highly expressed in patients with MM, and membrane PVR expression showed significant correlation with soluble PVR levels. Moreover, PVR expression was significantly associated with Revised-International Staging System stage, presence of extramedullary plasmacyoma and bone lesions, percentage of bone marrow plasma cells, and β2-microglobulin levels, suggesting a possible role in advanced stage and metastasis. Furthermore, we found that TIGIT expression was significantly correlated with the percentage of bone marrow plasma cells. Patients with high PVR expression had significantly shorter overall and progression-free survival, and PVR expression was identified as an independent prognostic factor for poor survival in MM. These findings indicated that PVR expression is associated with MM stage and poor prognosis, suggesting PVR expression as a potential prognostic marker for MM.

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Immune‐dysregulation harnessing in myeloid neoplasms

Sharifi,

Xu,

Nasiri

et al. 2024

Cancer Medicine

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Myeloid malignancies arise in bone marrow microenvironments and shape these microenvironments in favor of malignant development. Immune suppression is one of the most important stages in myeloid leukemia progression. Leukemic clone expansion and immune dysregulation occur simultaneously in bone marrow microenvironments. Complex interactions emerge between normal immune system elements and leukemic clones in the bone marrow. In recent years, researchers have identified several of these pathological interactions. For instance, recent works shows that the secretion of inflammatory cytokines such as tumor necrosis factor‐α (TNF‐α), from bone marrow stromal cells contributes to immune dysregulation and the selective proliferation of JAK2V617F+ clones in myeloproliferative neoplasms. Moreover, inflammasome activation and sterile inflammation result in inflamed microenvironments and the development of myelodysplastic syndromes. Additional immune dysregulations, such as exhaustion of T and NK cells, an increase in regulatory T cells, and impairments in antigen presentation are common findings in myeloid malignancies. In this review, we discuss the role of altered bone marrow microenvironments in the induction of immune dysregulations that accompany myeloid malignancies. We also consider both current and novel therapeutic strategies to restore normal immune system function in the context of myeloid malignancies.

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Increased TIGIT expressing NK cells with dysfunctional phenotype in AML patients correlated with poor prognosis

Cited by 42 publications

References 42 publications

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

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

PVR (CD155) Expression as a Potential Prognostic Marker in Multiple Myeloma

Immune‐dysregulation harnessing in myeloid neoplasms

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