Vδ2 T cell subsets, defined by PD-1 and TIM-3 expression, present varied cytokine responses in acute myeloid leukemia patients

Wu, Kan; Feng, Juan; Xiu, Yanghui; Li, Zhifeng; Lin, Zhijuan; Zhao, Haijun; Zeng, Hanyan; Xia, Weilin; Yu, Lian; Xu, Bing

doi:10.1016/j.intimp.2019.106122

Cited by 28 publications

(35 citation statements)

References 31 publications

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“…In AML patients who received allo-HSCT, a higher γδ T cell count, which is an important early source of TNF-α and IFN-γ, predicted a better prognosis. A recent study found that PD-1 + TIM-3 + Vδ2 T cells, PD-L1, and HMGB1 were significantly higher in AML patients than in healthy controls, suggesting that PD-1 alone is insufficient to indicate functional impairment, and Vδ2 T cells may require anti-TIM-3 inhibition for functional revival [157].…”

Section: The Potential Clinical Applications Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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High mobility group box 1 (HMGB1) is a nonhistone chromatin-associated protein that has been widely reported to play a pivotal role in the pathogenesis of hematopoietic malignancies. As a representative damage-associated molecular pattern (DAMP), HMGB1 normally exists inside cells but can be secreted into the extracellular environment through passive or active release. Extracellular HMGB1 binds with several different receptors and interactors to mediate the proliferation, differentiation, mobilization, and senescence of hematopoietic stem cells (HSCs). HMGB1 is also involved in the formation of the inflammatory bone marrow (BM) microenvironment by activating proinflammatory signaling pathways. Moreover, HMGB1-dependent autophagy induces chemotherapy resistance in leukemia and multiple myeloma. In this review, we systematically summarize the emerging roles of HMGB1 in carcinogenesis, progression, prognosis, and potential clinical applications in different hematopoietic malignancies. In summary, targeting the regulation of HMGB1 activity in HSCs and the BM microenvironment is highly beneficial in the diagnosis and treatment of various hematopoietic malignancies.

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Section: The Potential Clinical Applications Of Hmgb1mentioning

confidence: 99%

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

et al. 2020

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“…Most Vd2gd T cells are Vd1 + cells that distribute in tissues and exhibit adaptive-like features (7). Each subpopulation is further subject to the regulation of local microenvironment and antigen stimuli and then differentiates into diverse functional populations, which is similar to Th1, Th2, Th17, and Treg cells, or expresses a different array of molecules related to cytotoxicity (e.g., perforin, granzyme B, Fas ligand, and CD107a) (20) and activation/exhaustion (e.g., CD25, PD1 and TIM-3) (21). Therefore, the distinct results described above could be due to the functional heterogeneity of gd T-cell subsets.…”

Section: Introductionmentioning

confidence: 99%

Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion

et al. 2021

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Previous studies have reported the involvement of γδ T cells in recurrent spontaneous abortion (RSA); however, both pathogenic and protective effects were suggested. To interrogate the role of γδ T cells in RSA, peripheral blood from RSA patients and healthy women with or without pregnancy were analyzed for γδ T cells by flow cytometry (n = 9–11 for each group). Moreover, the decidua from pregnant RSA patients and healthy controls (RSA-P and HC-P group, respectively) was simultaneously stained for γδ T cells by immunohistochemistry (IHC) and bulk sequenced for gene expression. Our results demonstrated that the frequencies of peripheral γδ T cells and their subpopulations in RSA patients were comparable to that in healthy subjects, but the PD1 expression on Vδ2+ cells was increased in pregnant patients. Furthermore, peripheral Vδ2+ cells in RSA-P patients demonstrated significantly increased expression of CD107a, as compared to that in pregnant healthy controls. In addition, RSA-P patients had higher proportion of IL-17A-secreting but not IL-4-secreting Vδ2+ cells compared to the control groups. In decidua, an inflammatory microenvironment was also evident in RSA-P patients, in which CCL8 expression and the infiltration of certain immune cells were higher than that in the HC-P group, as revealed by transcriptional analysis. Finally, although the presence of γδ T cells in decidua could be detected during pregnancy in both RSA patients and healthy subjects by multicolor IHC analysis, the expression of CD107a on γδ T cells was markedly higher in the RSA-P group. Collectively, our results indicated that the increased activation, cytotoxicity, and inflammatory potential of peripheral and/or local γδ T cells might be responsible for the pathogenesis of RSA. These findings could provide a better understanding of the role of γδ T cells in RSA and shed light on novel treatment strategies by targeting γδ T cells for RSA patients.

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“…These TIM-3 + Vδ2 cells showed reduced proliferation and cytokine production following stimulation, which was associated with asymptomatic malaria infection [ 141 ]. More recently, Vδ2 cells isolated from acute myeloid leukemia (AML) and colorectal cancer patients displayed increased TIM-3 expression and a dysfunctional phenotype when compared to healthy controls [ 142 , 143 , 144 ]. Activation of TIM-3 with Gal-9 lowered Vδ2 cell cytotoxicity towards colon cancer cell lines by reducing production of perforin and granzyme B through the ERK1/2 pathway [ 144 ].…”

Section: Tim-3mentioning

confidence: 99%

“…In addition, Vδ2 cells from AML patients showed impaired proliferative capacity upon IL-21 stimulation, which was restored by blocking TIM-3 signaling [ 142 ]. When both TIM-3 and PD-1 expression were investigated, Vδ2 cells that co-expressed TIM-3 and PD-1 exhibited the lowest production of IFN-γ and TNF-α compared to all other Vδ2 populations [ 143 ]. Interestingly, anti-TIM-3 or anti-TIM-3 plus anti-PD-1 blocking antibodies, but not anti-PD-1 alone, increased cytokine production [ 143 ], highlighting the importance of TIM-3 inhibition for functional restoration of γδ T cells.…”

Section: Tim-3mentioning

confidence: 99%

Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

Tardos

Baglioni

Bekiaris

2021

Cancers

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In recent years, checkpoint inhibitor (CPI) therapy has shown promising clinical responses across a broad range of cancers. However, many patients remain unresponsive and there is need for improvement. CPI therapy relies on antibody-mediated neutralization of immune inhibitory or checkpoint receptors (ICRs) that constitutively suppress leukocytes. In this regard, the clinical outcome of CPI therapy has primarily been attributed to modulating classical MHC-restricted αβ T cell responses, yet, it will inevitably target most lymphoid (and many myeloid) populations. As such, unconventional non-MHC-restricted gamma delta (γδ) T, mucosal associated invariant T (MAIT) and natural killer T (NKT) cells express ICRs at steady-state and after activation and may thus be affected by CPI therapies. To which extent, however, remains unclear. These unconventional T cells are polyfunctional innate-like lymphocytes that play a key role in tumor immune surveillance and have a plethora of protective and pathogenic immune responses. The robust anti-tumor potential of γδ T, MAIT, and NKT cells has been established in a variety of preclinical cancer models and in clinical reports. In contrast, recent studies have documented a pro-tumor effect of innate-like T cell subsets that secrete pro-inflammatory cytokines. Consequently, understanding the mechanisms that regulate such T cells and their response to CPI is critical in designing effective cancer immunotherapies that favor anti-tumor immunity. In this Review, we will discuss the current understanding regarding the role of immune checkpoint regulation in γδ T, MAIT, and NKT cells and its importance in anti-cancer immunity.

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Vδ2 T cell subsets, defined by PD-1 and TIM-3 expression, present varied cytokine responses in acute myeloid leukemia patients

Cited by 28 publications

References 31 publications

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

High mobility group box 1 (HMGB1): a pivotal regulator of hematopoietic malignancies

Activated γδ T Cells With Higher CD107a Expression and Inflammatory Potential During Early Pregnancy in Patients With Recurrent Spontaneous Abortion

Inhibiting the Unconventionals: Importance of Immune Checkpoint Receptors in γδ T, MAIT, and NKT Cells

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