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AIM: To characterize the distribution of T cell immunoglobulin mucin-domain-containing-3 (Tim-3) within the exhausted T cells in patients with newly diagnosed acute myeloid leukemia (AML) and AML in complete remission. METHODS: Tim-3 expression and coexpression with PD-1, CD244, and CD57 in CD3+, CD4+, and CD8+T cells were analyzed by multicolored fluorescent flow cytometry in peripheral blood from 28 newly diagnosed, untreated AML patient and 12 cases with AML in complete remission, 23 healthy individuals served as control. RESULTS: Increasing Tim-3+CD244+ and Tim-3+CD57+ in CD3+, CD4+, and CD8+ T cells were found in AML and AML-CR groups in comparison with healthy controls. Similarly, increasing Tim-3 coexpression PD-1+ CD3+/CD4+/CD8+ T cells were found in AML group. A high tendency of PD-1+Tim-3+CD3+/CD4+/CD8+ T cells was detected in the AML-M4 subtype group followed by the M2 group, and a low tendency was found in the M3 group. Moreover, Tim-3+CD244+CD8+ T cells were found to be significantly higher in the M4 than that in M3 group. Dynamic changes of Tim-3+ T cells in AML patients who achieved CR after chemotherapy at different time points showed that Tim-3+ T cell subsets were evidently decreased; however, they remained at a higher level in most AML-CR patients. CONCLUSION: We made a novel observation on distribution of Tim-3+CD244+, Tim-3+CD57+, and Tim-3+PD-1+ T cells in patients with AML. Chemotherapy is incapable of resolving immunosuppression in some cases with AML in CR status.
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Antígenos CD57/genética , Leucemia Mieloide Aguda/genética , Receptor de Muerte Celular Programada 1/genética , Familia de Moléculas Señalizadoras de la Activación Linfocitaria/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , Adulto JovenRESUMEN
BACKGROUND: Altered expression of T cell immune inhibitory receptors may result in immunosuppression and associate with the poor prognosis of leukemia patients in which the leukemic bone marrow (BM) microenvironment may contribute to such immunosuppression. We found higher numbers of programmed death-1 (PD-1) + exhausted T cells in peripheral blood (PB) from acute myeloid leukemia (AML) patients. To investigate the leukemic BM influence on immunosuppression, we further compared the distributions of PD-1 and T cell immunoglobulin mucin-3 (Tim-3) and the exhausted T cell phenotype in PB and BM from AML patients and characterized their relationship with clinical outcome. METHODS: PB and BM samples from 15 patients with newly diagnosed AML were collected and analyzed for the expression of PD-1, Tim-3, CD244, and CD57 on CD3+, CD4+, and CD8+ T cells by multicolor flow cytometry. RESULTS: The proportions of PD-1 + CD3+ and PD-1 + CD8+ T cells were significantly higher in BM compared with PB. Similarly, higher PD-1 + CD244 + CD3+ and PD-1 + CD244 + CD8+ T cells were found in BM, and an increased tendency for PD-1 + CD244 + CD4+ T cells was also detected in this group. In contrast, increased Tim-3 + CD4+/Tim-3 + CD244 + CD4+ T cells were predominant in BM compared with PB, but there was no statistically significant difference in Tim-3 + CD8+ T cells. Moreover, PD-1 and Tim-3 double-positive CD3+/CD4+/CD8+ T cells were significantly increased in the BM group. In addition, a higher proportion of PD-1 + Tim-3 + CD3+ T cells in the BM and PD-1 + Tim-3 + CD4+ T cells in PB was detected in non-complete remission (NCR) compared with complete remission (CR) patients after first-cycle chemotherapy. CONCLUSIONS: Upregulation of PD-1 and Tim-3 and the exhausted phenotype of CD4+ and CD8+ T cells in the BM of AML patients may contribute to mediating the leukemic immunosuppressive microenvironment, and increased PD-1 + Tim-3+ CD8+ T cells may be related to T cell dysfunction in AML, which may influence clinical outcome.
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AIM: Immune suppression based on alternative regulation of immune checkpoint proteins, for example, programmed cell death receptor-1 (PD-1) and cytotoxic T lymphocyte-associated molecule-4 (CTLA-4), which results in T-cell exhaustion, contributes to cancer development and progression. In this study, we sought to characterize the distribution of CTLA-4 and T-cell lymphocyte activation gene-3 (LAG-3) expression on exhausted T cells in different T-cell subsets from patients with acute myeloid leukemia (AML). METHODS: The coexpression of CTLA-4 and LAG-3 on exhausted CD244+ and CD57+ T cells from the CD3+ , CD4+ , and CD8+ T-cell subsets in peripheral blood from 12 patients with newly diagnosed AML was analyzed by multicolor flow cytometry assay. RESULTS: A significantly higher percentage of CTLA-4+ CD3+ , CD4+ and CD8+ T cells was found in patients with AML. In addition, higher numbers of both CTLA-4+ CD244+ and CTLA-4+ CD57+ CD3+ T cells were detected. Interestingly, the increased CTLA-4+ CD244+ T cells were predominantly CD4+ T cells. In contrast, the increased CTLA-4+ CD57+ T cells primarily consisted of the CD8+ T-cell subset. A high proportion of LAG-3+ T cells was found in only a few cases with AML; however, a significantly higher proportion of coexpression of CTLA-4 and LAG-3 in the CD3+ and CD8+ T-cell subsets was detected. CONCLUSION: We for the first time observed higher CTLA-4+ CD244+ CD4+ , CTLA-4+ CD57+ CD8+ , CTLA-4+ LAG-3+ CD3+ and CTLA-4+ LAG-3+ CD8+ T cells in patients with AML, whereas the upregulated expression of LAG-3 on T cells was only found in a subset of the cases. These data may provide further information by complementing the heterogeneity of immune checkpoints expression in AML.
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Antígeno CTLA-4/metabolismo , Leucemia Mieloide Aguda/genética , Linfocitos T Citotóxicos/metabolismo , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Leucemia Mieloide Aguda/patología , Masculino , Persona de Mediana Edad , PronósticoRESUMEN
T cell inhibitory receptors play important role in maintaining T cell homeostasis. The feature of such negative costimulator signal transduction pathway in cord blood (CB) T cells remains unclear. In this study, the expression levels of T cell inhibitory receptors including programmed death-1 (PD-1), cytotoxic T lymphocyte antigen-4 (CTLA-4), T cell immunoglobulin mucin-3 (Tim-3), lymphocyte activation gene-3 (LAG-3) and B and T lymphocyte attenuator (BTLA) were characterized in CB and compared with peripheral blood (PB). Significant lower expression of PD-1, CTLA-4, LAG-3 and BTLA was found in CB, while similar expression level of Tim-3 was showed between CB and PB. Together, different expression pattern of such T cell inhibitory receptor in CB is worthy to further discuss their role on immune response when CB is used in cord blood stem cell transplantation as well as allogeneic chimeric antigen receptor T-cell producing.
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The limited application of immunotherapy in acute myeloid leukemia (AML) may be due to poor understanding of the global T cell immune dysfunction in AML. In this study, we analyzed the distribution characteristics of 24 TCR Vß subfamilies in CD3+, CD4+, and CD8+ T cells in AML patients and healthy controls. The percentage of TCR Vß subfamily T cells was predominately lower in most AML cases, while it was increased in some cases. TCR Vß2+T cells were increased in AML, particularly TCR Vß2+CD4+T cells, which were significantly higher. To further address the immunosuppression in different Vß subfamilies, we characterized the distribution of program death-1 (PD-1)+T cells in TCR Vß subfamilies of CD4+ and CD8+T cells. Significantly higher levels of PD-1+Vß+T cells were found for most Vß subfamilies in most AML cases. A higher percentage of PD-1+Vß2+T cells with a high number of Vß2+T cells was found in all of the CD3+, CD4+, and CD8+ T cell subsets. Moreover, increasing PD-1+Vß7.2, Vß8+, Vß14+, Vß16+, and Vß22+CD8+T cells were distributed in the AML-M5 subtype group compared with the AML-M3 group. In addition, higher PD-1+ Vß5.2+ and PD-1+ Vß12+CD8+T cells were associated with AML patients who had a poor response to chemotherapy. In conclusion, increased PD-1+Vß+T cells is a common characteristic of AML, higher PD-1+Vß2+T cells may be associated with a low antileukemia effect, and higher PD-1+Vß5.2+ and PD-1+Vß12+CD8+T cells may be related to poor prognosis in AML. These characteristics may be worth considering as immune biomarkers for clinical outcome in AML.
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Linfocitos T CD8-positivos/inmunología , Leucemia Mieloide Aguda/inmunología , Receptor de Muerte Celular Programada 1/metabolismo , Receptores de Antígenos de Linfocitos T alfa-beta/metabolismo , Adulto , Anciano , Femenino , Humanos , Leucemia Mieloide Aguda/tratamiento farmacológico , Masculino , Persona de Mediana Edad , Resultado del Tratamiento , Adulto JovenRESUMEN
AIM: The immunosuppressive microenvironment plays a crucial role in T-cell immunodeficiency in multiple myeloma (MM). Overexpression of T-cell immunosuppressive receptors, including programmed death-1 (PD-1) and T-cell immunoglobulin and mucin-domain-containing-3 (Tim-3), may be related to tumor immunosuppression and poor prognosis, and the malignant bone marrow (BM) microenvironment may contribute to such immunosuppression. The purpose of this study was to analyze the distribution of PD-1+ and/or Tim-3+ T cells in different T-cell subset in patients with MM. METHODS: The expression of PD-1 and Tim-3 with exhausted (CD244+ and CD57+ ) CD3+ , CD4+ and CD8+ T cells between BM and peripheral blood (PB) from 10 patients with untreated MM was detected by multicolor flow cytometry assay. RESULTS: A significant increase in both PD-1+ CD57+ and Tim-3+ CD57+ CD3+ T cells and PD-1+ Tim-3+ CD3+ T cells was detected in PB from patients with MM compared with 10 healthy individuals (HIs), and the alteration was mostly in the CD8+ T-cell subset. Significant higher percentage of PD-1+ CD3+ T cells was found in BM compared with PB from patients with MM. The level of PD-1+ Tim-3+ CD3+ , CD4+ , and CD8+ T cells was high in BM group compared with PB. Moreover, PD-1+ CD244+ or PD-1+ CD57+ CD3+ T cells, particularly PD-1+ CD244+ and PD-1+ CD57+ CD8+ T cells were significantly higher in BM than in PB. In addition, limited dynamic detection data from three MM cases who achieved complete remission after treatment showed that the numbers of either PD-1+ or PD-1+ Tim-3+ T cells in different T-cell subsets were decreased in both BM and PB. CONCLUSION: We characterized the distribution of PD-1 and TIM-3 concurrent with exhausted CD3+ , CD4+ and CD8+ T cells between BM and PB from patients with MM. Higher numbers of PD-1+ CD244+ or PD-1+ CD57+ CD3+ T cells in BM from patients with MM may contribute to mediate the BM immunosuppressive microenvironment. Although heterogeneous alterations in Tim-3+ T cells may represent a complex immunosuppressive pattern in MM. Overall, higher levels of PD-1+ CD244+ or PD-1/Tim-3+ CD57+ CD8+ T cells may be a major reason for lower T-cell activation and T-cell immunodeficiency in MM.
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Linfocitos T CD8-positivos/inmunología , Receptor 2 Celular del Virus de la Hepatitis A/inmunología , Mieloma Múltiple/inmunología , Receptor de Muerte Celular Programada 1/inmunología , Subgrupos de Linfocitos T/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Femenino , Humanos , Inmunofenotipificación , Masculino , Persona de Mediana Edad , FenotipoRESUMEN
A new class of organic cathode interfacial layer (CIL) materials based on isoindigo derivatives (IID) substituted with pyridinium or sulfonate zwitterion groups were designed, synthesized, and applied in polymer solar cells (PSCs) with PTB7:PC71BM (PTB7: polythieno[3,4-b]-thiophene-co-benzodithiophene and PC71BM: [6,6]-phenyl C71-butyric acidmethyl ester) as an active layer. Compared with the control device, PSCs with an IID-based CIL show simultaneous enhancement of open-circuit voltage (Voc), short-circuit current (Jsc), and fill factor (FF). Systematic optimizations of the central conjugated core and side flexible alcohol-soluble groups demonstrated that isoindigo-based CIL material with thiophene and sulfonate zwitterion substituent groups can efficiently enhance the PSC performance. The highest power conversion efficiency (PCE) of 9.12%, which is 1.75 times that of the control device without CIL, was achieved for the PSC having an isoindigo-based CIL. For the PSCs with an isoindigo-based CIL, the molecule-dependent performance property studies revealed that the central conjugated core with D-A-D characteristics and the side chains with sulfonate zwitterions groups represents an efficient strategy for constructing high performance CILs. Our study results may open a new avenue toward high performance PSCs.
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Organic optoelectronics are promising technologies for energy conversion. However, the electrode interlayer, a key material between active layers and conducting electrodes that controls the transport of charge carriers in and out of devices, is still a chemical challenge. Herein, we report a class of porous organic polymers with tunable work function as hole- and electron-selective electrode interlayers. The network with organoborane and carbazole units exhibits extremely low work-function-selective electron flow; while upon ionic ligation and electro-oxidation, the network significantly increases the work function and turns into hole conduction. We demonstrate their outstanding functions as anode and cathode interlayers in energy-converting solar cells and light-emitting diodes.
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Conjugated microporous polymers are a unique class of polymers that combine extended π-conjugation with inherent porosity. However, these polymers are synthesized through solution-phase reactions to yield insoluble and unprocessable solids, which preclude not only the evaluation of their conducting properties but also the fabrication of thin films for device implementation. Here, we report a strategy for the synthesis of thin films of π-conjugated microporous polymers by designing thiophene-based electropolymerization at the solution-electrode interface. High-quality films are prepared on a large area of various electrodes, the film thickness is controllable, and the films are used for device fabrication. These films are outstanding hole conductors and, upon incorporation of fullerenes into the pores, function as highly efficient photoactive layers for energy conversions. Our film strategy may boost the applications in photocatalysis, energy storage, and optoelectronics.
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We present a furan-flanked DPP copolymer, poly{3,6-difuran-2-yl-2,5-di(2-octyldodecyl)-pyrrolo [3,4-c]pyrrole-1,4-dione-altthienylenevinylene} (PDVF-8), and highlight the improvement in the power conversion efficiency (PCE) of polymer solar cells (PSCs) based on the PDVF-8 as an electron donor via solvent additive and methanol treatment. When 3 vol% 1,8-diiodooctane (DIO) or 1-chloronaphthalene (CN) were used as a solvent additive to the PDVF-8:PC71BM solution in chloroform (CF), the PCE can increase from 0.79% to 3.73% or 4.26%. Methanol treatment (MT) can further enhance the PCE to 4.03% (DIO) and 4.69% (CN). The effect of the solvent additives (DIO and CN) and MT on the phase separation of the PDVF-8:PC71BM thin film has been investigated in detail using atomic force microscopy, transmission electron microscopy (TEM), TEM-energy dispersive spectroscopy and X-ray photoemission spectroscopy depth profiling.
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9-Arylidene-9H-fluorene containing donor-acceptor (D-A) alternating polymers P1 and P2 were synthsized and used for the fabrication of polymer solar cells (PSCs). High and low molecular weight P1 (HMW-P1 and LMW-P1) and high molecular weight P2 were prepared to study the influence of molecular weight and the position of alkoxy chains on the photovoltaic performance of PSCs. HMW-P1:PC71BM-based PSCs fabricated from 1,2-dichlorobenzene (DCB) solutions showed a power conversion efficiency (PCE) of 6.26%, while LMW-P1:PC71BM-based PSCs showed poor photovoltaic performance with a PCE of only 2.75%. PCE of HMW-P1:PC71BM-based PSCs was further increased to 6.52% with the addition of 1,8-diiodooctane (DIO) as the additive. Meanwhile, PCE of only 2.51% was obtained for P2:PC71BM-based PSCs. The results indicated that the position of alkoxy substituents on the 9-arylidene-9H-fluorene unit and the molecular weight of polymers are very crucial to the photovoltaic performance of PSCs.
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Film-like conjugated microporous polymers (CMPs) are fabricated by the novel strategy of carbazole-based electropolymerization. The CMP film storing a mass of counterions acting as an anode interlayer provides a significant power-conversion efficiency of 7.56% in polymer solar cells and 20.7 cd A(-1) in polymer light-emitting diodes, demonstrating its universality and potential as an electrode interlayer in organic electronics.