scholarly journals Elevated coinhibitory molecule TIGIT mediates T cell exhaustion in septic patients

2021 ◽  
Author(s):  
Yini Sun ◽  
Renyu Ding ◽  
Yukun Chang ◽  
Jiuming Li ◽  
Xiaochun Ma
Keyword(s):  
T Cells ◽  
T Cell ◽  
Crucial Role ◽  
Cell Function ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract Background: Sepsis-induced T cell exhaustion that is characterized by upregulated coinhibitory molecules and decreased cytokines release plays a crucial role in the immunosuppression during sepsis. Although PD-1 has shown a promising target to interfere with T cells dysfunction, the role of other coinhibitory receptors in sepsis remains largely elusive. Recently, it has been demonstrated that the coinhibitory molecule TIGIT more reliably identified exhausted T cells than PD-1. The aim of the study was to identify the expression of TIGIT on lymphocytes and the crucial role of TIGIT in modulating T cell function in septic patients. Methods: Twenty-five patients with sepsis and seventeen healthy controls were prospectively enrolled. Peripheral blood was obtained from septic patients within 24 hours after diagnosis of sepsis, as were healthy controls. TIGIT and other coinhibitory/costimulatory molecules expression on lymphocyte subsets was quantitated by flow cytometry. The relationship between TIGIT expression and clinical parameters was simultaneously evaluated. The function T cell from septic patients was assayed via stimulated cytokine secretion. Ex vivo functional assays were also conducted.Results: In the early stage of sepsis, patients exhibited higher levels of TIGIT on T cells relative to healthy donors, especially in the septic shock patients. Elevated frequencies of TIGIT + T cells positively correlated with the severity of organ failure and inflammatory responses in septic patients. TIGIT + T cells expressed higher levels of PD-1 and lower CD226. Further, elevated expression of TIGIT inhibited the release of cytokines including TNF, IFN-γ and IL-2 by CD4 + and CD8 + T cells. Strikingly, ex vivo blockade of TIGIT using anti-TIGIT antibody restored the frequencies of cytokine-producing T cells. Conclusions: These data illustrate TIGIT as a novel marker of exhausted T cells and suggest TIGIT may be a novel immunotherapeutic target during sepsis.

scholarly journals Local and Systemic CD4+ T Cell Exhaustion Reverses with Clinical Resolution of Pulmonary Sarcoidosis

2017 ◽  
Vol 2017 ◽  
pp. 1-14 ◽  
Author(s):  
Charlene Hawkins ◽  
Guzel Shaginurova ◽  
D. Auriel Shelton ◽  
Jose D. Herazo-Maya ◽  
Kyra A. Oswald-Richter ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Pulmonary Sarcoidosis ◽  
Cytokine Expression ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Proliferative Capacity ◽  
Cell Exhaustion ◽  
Th1 Cytokine

Investigation of the Th1 immune response in sarcoidosis CD4+ T cells has revealed reduced proliferative capacity and cytokine expression upon TCR stimulation. In other disease models, such cellular dysfunction has been associated with a step-wise, progressive loss of T cell function that results from chronic antigenic stimulation. T cell exhaustion is defined by decreased cytokine production upon TCR activation, decreased proliferation, increased expression of inhibitory cell surface receptors, and increased susceptibility to apoptosis. We characterized sarcoidosis CD4+ T cell immune function in systemic and local environments among subjects undergoing disease progression compared to those experiencing disease resolution. Spontaneous and TCR-stimulated Th1 cytokine expression and proliferation assays were performed in 53 sarcoidosis subjects and 30 healthy controls. PD-1 expression and apoptosis were assessed by flow cytometry. Compared to healthy controls, sarcoidosis CD4+ T cells demonstrated reductions in Th1 cytokine expression, proliferative capacity (p<0.05), enhanced apoptosis (p<0.01), and increased PD-1 expression (p<0.001). BAL-derived CD4+ T cells also demonstrated multiple facets of T cell exhaustion (p<0.05). Reversal of CD4+ T cell exhaustion was observed in subjects undergoing spontaneous resolution (p<0.05). Sarcoidosis CD4+ T cells exhibit loss of cellular function during progressive disease that follows the archetype of T cell exhaustion.

scholarly journals VitaminD3 Regulates T Cell Immune Responses in Allergen and Rhinovirus Induced Asthma

2021 ◽  
Author(s):  
Susetta Finotto ◽  
Patricia Haag ◽  
Darja Andreev ◽  
Nina Li ◽  
Alexander Kiefer ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Murine Model ◽  
Peripheral Blood ◽  
Serum Levels ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Asthmatic Children ◽  
Rhinovirus Infection

Abstract Background: Serum 25(OH)-Vitamin D3 (VitD3) deficiency during infancy has been associated with asthma. The potential therapeutic role of VitD3 given in the airways and its interference with the allergen and Rhinovirus was the objective of this study. Methods: In two cohorts of children with and without asthma, serum levels of the C-reactive protein (CRP) were correlated to Serum VitD3 and in peripheral blood T cell inhibitor marker Programmed cell death protein 1 (PD1) mRNA was analyzed. In a murine model, VitD3 was given intranasally in vivo and in vitro to lung cells with allergen and Rhinovirus. Results: In the cohorts of pre-school age children without (control) asthma, CRP and VitD3 levels inversely correlated. In preschool asthmatic children that did not receive VitD3 supplementation as infant had more episode of asthma exacerbation associated with high CRP serum level. In peripheral blood cells from control but not asthmatic children with higher serum levels of VitD3 had lower PD1 mRNA levels. In murine model, OVA intranasal challenge induced Innate Lymphoid Cells type 2 (ILC2)-associated markers and Eosinophils in BALF and VitD3 inhibited lung inflammation and ILC2 markers. Furthermore, VitD3 given intranasally, induced CD4+T cells and reduced PD1, T regulatory cells in the lung. Similarly, VitD3 had a suppressive role on CD4+PD1+ T cells involved in T cell exhaustion in the airways in the absence of ST2 after Rhinovirus infection. Conclusion: These data support an inhibitory role of VitD3 on T cell exhaustion after allergen and rhinovirus infection that is relevant for pediatric asthma.

scholarly journals Metabolic Reprogramming and Intervention During T Cell Exhaustion

2021 ◽  
Author(s):  
Fei Li ◽  
Huiling Liu ◽  
Dan Zhang ◽  
Bingdong Zhu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cell Function ◽  
Cell Metabolism ◽  
T Cell Exhaustion ◽  
Naive T Cells ◽  
Cell Exhaustion ◽  
Naïve T Cells ◽  
T Cell Function ◽  
Prevention And Treatment

Recent studies have shown that T cell metabolism has become a key regulator of T cell function and even can determine T cell function at last. Naïve T cells use fatty acid oxidation (FAO) to meet their energetic demands. Effector T cells mainly rely on aerobic glycolysis to supply energy and synthesize intermediate products. Similar to naïve T cells, memory T cells primarily utilize FAO for energy. Exhausted T cells, which can be induced by continuous activation of T cells upon persistently chronic infections such as tuberculosis, mainly rely on glycolysis for energy. The prevention and treatment of T cell exhaustion is facing great challenges. Interfering T cell metabolism may achieve the goal of prevention and treatment of T cell exhaustion. In this review, we compiled the researches related to exhausted T cell metabolism and put forward the metabolic intervention strategies to reverse T cell exhaustion at different stages to achieve the purpose of preventing and treating T cell exhaustion.

scholarly journals Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas

2018 ◽  
Vol 86 (9) ◽  
Author(s):  
Eileen A. Wong ◽  
Louis Joslyn ◽  
Nicole L. Grant ◽  
Edwin Klein ◽  
Philana Ling Lin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Cell Function ◽  
Cell Activity ◽  
Intrinsic Property ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Content Type ◽  
Cell Exhaustion

ABSTRACTThe hallmarks of pulmonaryMycobacterium tuberculosisinfection are lung granulomas. These organized structures are composed of host immune cells whose purpose is to contain or clear infection, creating a complex hub of immune and bacterial cell activity, as well as limiting pathology in the lungs. Yet, given cellular activity and the potential for frequent interactions between host immune cells andM. tuberculosis-infected cells, we observed a surprisingly low quantity of cytokine-producing T cells (<10% of granuloma T cells) in our recent study ofM. tuberculosisinfection within nonhuman primate (NHP) granulomas. Various mechanisms could limit T cell function, and one hypothesis is T cell exhaustion. T cell exhaustion is proposed to result from continual antigen stimulation, inducing them to enter a state characterized by low cytokine production, low proliferation, and expression of a series of inhibitory receptors, the most common being PD-1, LAG-3, and CTLA-4. In this work, we characterized the expression of inhibitory receptors on T cells and the functionality of these cells in tuberculosis (TB) lung granulomas. We then used these experimental data to calibrate and inform an agent-based computational model that captures environmental, cellular, and bacterial dynamics within granulomas in lungs duringM. tuberculosisinfection. Together, the results of the modeling and the experimental work suggest that T cell exhaustion alone is not responsible for the low quantity ofM. tuberculosis-responsive T cells observed within TB granulomas and that the lack of exhaustion is likely an intrinsic property of granuloma structure.

scholarly journals Expanded antigen-experienced CD160+CD8+effector T cells exhibit impaired effector functions in chronic lymphocytic leukemia

2021 ◽  
Vol 9 (4) ◽  
pp. e002189
Author(s):  
Najmeh Bozorgmehr ◽  
Isobel Okoye ◽  
Olaide Oyegbami ◽  
Lai Xu ◽  
Amelie Fontaine ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Effector T Cells ◽  
Lymphocytic Leukemia ◽  
Healthy Controls ◽  
T Cell Exhaustion ◽  
Inhibitory Receptors ◽  
Cell Exhaustion ◽  
Effector Functions ◽  
Cell Effector

BackgroundT cell exhaustion compromises antitumor immunity, and a sustained elevation of co-inhibitory receptors is a hallmark of T cell exhaustion in solid tumors. Similarly, upregulation of co-inhibitory receptors has been reported in T cells in hematological cancers such as chronic lymphocytic leukemia (CLL). However, the role of CD160, a glycosylphosphatidylinositol-anchored protein, as one of these co-inhibitory receptors has been contradictory in T cell function. Therefore, we decided to elucidate how CD160 expression and/or co-expression with other co-inhibitory receptors influence T cell effector functions in patients with CLL.MethodsWe studied 56 patients with CLL and 25 age-matched and sex-matched healthy controls in this study. The expression of different co-inhibitory receptors was analyzed in T cells obtained from the peripheral blood or the bone marrow. Also, we quantified the properties of extracellular vesicles (EVs) in the plasma of patients with CLL versus healthy controls. Finally, we measured 29 different cytokines, chemokines or other biomarkers in the plasma specimens of patients with CLL and healthy controls.ResultsWe found that CD160 was the most upregulated co-inhibitory receptor in patients with CLL. Its expression was associated with an exhausted T cell phenotype. CD160+CD8+ T cells were highly antigen-experienced/effector T cells, while CD160+CD4+ T cells were more heterogeneous. In particular, we identified EVs as a source of CD160 in the plasma of patients with CLL that can be taken up by T cells. Moreover, we observed a dominantly proinflammatory cytokine profile in the plasma of patients with CLL. In particular, interleukin-16 (IL-16) was highly elevated and correlated with the advanced clinical stage (Rai). Furthermore, we observed that the incubation of T cells with IL-16 results in the upregulation of CD160.ConclusionsOur study provides a novel insight into the influence of CD160 expression/co-expression with other co-inhibitory receptors in T cell effector functions in patients with CLL. Besides, IL-16-mediated upregulation of CD160 expression in T cells highlights the importance of IL-16/CD160 as potential immunotherapy targets in patients with CLL. Therefore, our findings propose a significant role for CD160 in T cell exhaustion in patients with CLL.

scholarly journals Treatment-Free Intervals Mitigate T-Cell Exhaustion Induced By Continuous CD19xCD3-BiTE® Construct Stimulation in Vitro

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 44-45
Author(s):  
Nora Zieger ◽  
Alyssa Nicholls ◽  
Jan Wulf ◽  
Gerulf Hänel ◽  
Maryam Kazerani Pasikhani ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Research Funding ◽  
Cell Function ◽  
Granzyme B ◽  
T Cell Exhaustion ◽  
Specific Lysis ◽  
Cell Exhaustion ◽  
T Cell Function

The bispecific T-cell engager (BiTE®) blinatumomab is approved for treatment of relapsed/refractory B-cell precursor acute lymphoblastic leukemia and applied as continuous infusion over 28 days. The overall response rate to blinatumomab reported in clinical trials was 43 % and correlated to T-cell expansion (Zugmaier et al. 2015). In chronic viral infections, continuous antigen stimulation induces T-cell exhaustion, defined by phenotypic changes and functional impairment (Wherry 2011). Thus, we hypothesized that continuous BiTE® construct stimulation leads to T-cell exhaustion and that a treatment-free interval (TFI) reverses progressive T-cell dysfunction. To simulate continuous application of a BiTE® construct in vitro, T-cell long-term co-cultures were set up. Healthy donor T cells were stimulated in the presence of CD19+ OCI-Ly1 cells for 28 days with AMG 562, a half-life extended CD19 and CD3 specific BiTE® construct. T cells were harvested from the co-culture every 3-4 days between day 7 and 28 and assessed for markers of T-cell exhaustion: (1) AMG 562-mediated cytotoxicity of T cells was evaluated as specific lysis of CD19+ Ba/F3 target cells after 3 days, (2) T-cell expansion during the cytotoxicity assay was calculated as fold change (FC) of CD2+ counts, (3) Cytokine secretion of AMG 562-stimulated T cells was evaluated in co-culture supernatants by cytometric bead array (CBA) or after PMA/Ionomycine stimulation via intracellular cytokine staining (ICCS), (4) T-cell metabolic fitness was determined by Mito- and Glycolytic Stress Test using a Seahorse Analyzer, and (5) expression of the exhaustion-related transcription factor TOX was assessed by multiparameter flow cytometry. In order to assess the effect of a TFI on T-cell function, we cultured T cells and CD19+ OCI-Ly1 cells in the absence of AMG 562 from day 7-14 and 21-28 and compared their activity to T cells stimulated continuously with AMG 562. On day 7 of continuous (CONT) AMG 562 stimulation, we observed high cytotoxic and proliferative potential (% specific lysis=93±0.2, FC=2.9±0.2) as well as high IFN-g and TNF-a secretion analyzed by ICCS (% CD8+IFN-g+TNF-a+=23±6.7). However, cytotoxicity and proliferation decreased gradually until day 28 (% specific lysis=28±8.9; FC=0.6±0.1). CBA analysis confirmed decreasing secretion of IFN-g (day 3: 61113±12482, day 24: 3085±1351 pg/ml) and TNF-a (day 3: 1160±567, day 24: 43±7.6 pg/ml) as well as decreased IL-2 and granzyme B levels in culture supernatants. We furthermore observed highest mitochondrial fitness and basal glycolysis in T cells on day 7 of stimulation (basal OCR=2.2±0.6, maximal OCR=3.7±1.0, SRC=1.5±1.1 pmol/min/1000 cells, basal ECAR=2.0±0.4 mpH/min/1000 cells) which decreased until day 28 (basal OCR=0.4±0.2, maximal OCR=1.5±0.5, SRC=1.0±0.2 pmol/min/1000 cells, basal ECAR=0.5±0.2 mpH/min/1000 cells). In concordance, TOX increased during continuous stimulation (MFI ratio CD8+ day 7=6±0.8 to 12±0.8 on day 28). Strikingly, implementation of a TFI of 7 days led to superior cytotoxicity in T cells compared to continuously stimulated T cells (% specific lysis on day 14 CONT=34±4.2, TFI=99±2.2) and granzyme B production (CD8+; MFI ratio on day 14 CONT=124±11, TFI=303±34). Furthermore, increased proliferation during the cytotoxicity assay was observed in previously rested T cells (FC CONT=0.2±0.0, TFI=1.6±0.6). Although T cell function also decreased over time in TFI T cells, they maintained a strikingly higher cytotoxic potential (CONT=6±4.4, TFI=52±9.9) as well as higher granzyme B production (CONT=25±2, TFI=170±11) on day 28 compared to continuously stimulated T cells. In addition, TFI T cells showed increased IFN-g and TNF-a secretion after PMA/Ionomycine stimulation on day 28 (% CD8+IFN-g+TNF-a+ CONT=21±3.8, TFI=38±11.6). Our in vitro results demonstrate that continuous AMG 562 exposure negatively impacts T-cell function. Comprehensive analysis of T-cell activity in an array of functional assays suggests that continuous BiTE® construct exposure leads to T-cell exhaustion which can be mitigated through TFI. Currently, T cells from patients receiving blinatumomab are being analyzed to confirm the clinical relevance of our findings. Furthermore, RNA-Seq of continuously vs. intermittently AMG 562-exposed T cells will help us to understand underlying transcriptional mechanisms of BiTE® construct induced T-cell exhaustion. Disclosures Zieger: AMGEN Research Munich: Research Funding. Buecklein:Pfizer: Consultancy; Novartis: Research Funding; Celgene: Research Funding; Amgen: Consultancy; Gilead: Consultancy, Research Funding. Brauchle:AMGEN Inc.: Research Funding. Marcinek:AMGEN Research Munich: Research Funding. Kischel:AMGEN: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties. Subklewe:Gilead Sciences: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Morphosys: Research Funding; Seattle Genetics: Research Funding; AMGEN: Consultancy, Honoraria, Research Funding; Janssen: Consultancy; Roche AG: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Celgene: Consultancy, Honoraria.

Integrative Genomic Analysis of HIV-Specific CD8+ T Cells Reveals That PD-1 Inhibits T Cell Function by Upregulating the AP-1 Transcription Factor BATF.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 916-916
Author(s):  
Michael Quigley ◽  
Florencia Pereyra ◽  
Bjorn Nilsson ◽  
Quentin Eichbaum ◽  
Boris Julg ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Mouse Model ◽  
Cd8 T Cells ◽  
Cell Function ◽  
Genomic Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
T Cell Function

Abstract Abstract 916 T cells responding to chronic infections such as HIV lose the ability to secrete cytokines or to proliferate, functions critical for control of viral replication, in a process termed exhaustion. However the molecular mechanisms of T cell exhaustion are not understood, and few therapeutic targets to reinvigorate exhausted T cells have been identified. We therefore conducted a comprehensive genomic analysis of HIV-specific CD8+ T cells to identify the mechanisms underlying defective function in T cell exhaustion. We used Affymetrix microarrays to study gene expression profiles from sorted Gag-specific tetramer+ CD8+ T cells in two cohorts of HIV-infected individuals that differed in their extent of T cell exhaustion: a) Progressors (n=24), who show chronic elevation of viral load and have defects in HIV-specific T cell cytokine secretion, proliferation and survival; and b) Controllers (n=18), who show spontaneous control of viral replication and have relatively good HIV-specific T cell function. Profiles of Gag-specific CD8+ T cells (median 21,500 cells/sample) from progressors showed marked alterations in gene expression compared with those from controllers (n=518 genes upregulated in progressors, moderated t-statistic >2.0). There was highly significant similarity at the whole-genome level between dysfunctional Gag-specific CD8+ T cells from progressors and exhausted CD8+ T cells in the mouse model of chronic LCMV infection (gene set enrichment analysis, P=4.8e−005), suggesting that T cell exhaustion is associated with an evolutionarily conserved program of gene expression. Next, we determined whether this exhausted signature was influenced by inhibitory signaling via the receptor PD-1, an inhibitory receptor known to be upregulated in expression on exhausted T cells. We developed an in vitro model of PD-1 signaling and identified a unique signature of genes upregulated by PD-1 ligation. The signature of PD-1 induced genes was highly significantly upregulated in profiles from Gag-specific CD8+ T cells in HIV progressors compared to controllers (P=5e−006), and in exhausted CD8+ T cells from the LCMV mouse model (P=2e−004). Thus the signature of T cell exhaustion in humans and mice is driven in part by the consequences of PD-1 signaling. Finally, we asked whether the genes upregulated by PD-1 in exhausted T cells directly inhibit T cell function. PD-1 ligation upregulated the transcription factor BATF in HIV-specific CD8+ T cells and in exhausted CD8+ T cells from the mouse model of LCMV infection. Enforced expression of BATF, an inhibitory member of the AP-1 family, in normal human T cells inhibited proliferation (P=0.02) and IL2 secretion (P=4.5e-05). Infection with LCMV in BATF transgenic mice resulted in marked acceleration of T cell exhaustion compared to wild-type animals, indicating that BATF represses T cell effector functions. Silencing of BATF using shRNA in primary human T cells showed that it was required for PD-1 mediated inhibition of T cell function. In summary, our results demonstrate that 1) PD-1 ligation induces a conserved transcriptional program in exhausted HIV-specific CD8+ T cells and in exhausted LCMV-specific CD8+ T cells in the mouse; 2) this transcriptional program includes the upregulation of genes such as BATF that directly inhibit T cell function. Our data suggest that BATF causes the functional defects seen in T cell exhaustion, and represents a new therapeutic target to rescue T cell function in HIV infection. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blimp-1–mediated CD4 T cell exhaustion causes CD8 T cell dysfunction during chronic toxoplasmosis

2016 ◽  
Vol 213 (9) ◽  
pp. 1799-1818 ◽  
Author(s):  
SuJin Hwang ◽  
Dustin A. Cobb ◽  
Rajarshi Bhadra ◽  
Ben Youngblood ◽  
Imtiaz A. Khan
Keyword(s):  
T Cells ◽  
T Cell ◽  
Critical Role ◽  
Cd8 T Cell ◽  
Cd4 T Cell ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
T Cell Dysfunction

CD8, but not CD4, T cells are considered critical for control of chronic toxoplasmosis. Although CD8 exhaustion has been previously reported in Toxoplasma encephalitis (TE)–susceptible model, our current work demonstrates that CD4 not only become exhausted during chronic toxoplasmosis but this dysfunction is more pronounced than CD8 T cells. Exhausted CD4 population expressed elevated levels of multiple inhibitory receptors concomitant with the reduced functionality and up-regulation of Blimp-1, a transcription factor. Our data demonstrates for the first time that Blimp-1 is a critical regulator for CD4 T cell exhaustion especially in the CD4 central memory cell subset. Using a tamoxifen-dependent conditional Blimp-1 knockout mixed bone marrow chimera as well as an adoptive transfer approach, we show that CD4 T cell–intrinsic deletion of Blimp-1 reversed CD8 T cell dysfunction and resulted in improved pathogen control. To the best of our knowledge, this is a novel finding, which demonstrates the role of Blimp-1 as a critical regulator of CD4 dysfunction and links it to the CD8 T cell dysfunctionality observed in infected mice. The critical role of CD4-intrinsic Blimp-1 expression in mediating CD4 and CD8 T cell exhaustion may provide a rational basis for designing novel therapeutic approaches.

scholarly journals Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1

2021 ◽  
Vol 12 ◽  
Author(s):  
Ariana N. Renrick ◽  
Menaka C. Thounaojam ◽  
Maria Teresa P. de Aquino ◽  
Evan Chaudhuri ◽  
Jui Pandhare ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Microenvironment ◽  
Cell Function ◽  
T Cell Exhaustion ◽  
Functional Link ◽  
Cell Exhaustion ◽  
Cell Functions ◽  
Tumor Bearing ◽  
T Cell Function

Suppressive mechanisms operating within T cells are linked to immune dysfunction in the tumor microenvironment. We have previously reported using adoptive T cell immunotherapy models that tumor–bearing mice treated with a regimen of proteasome inhibitor, bortezomib - a dipeptidyl boronate, show increased antitumor lymphocyte effector function and survival. Here, we identify a mechanism for the improved antitumor CD8+ T cell function following bortezomib treatment. Intravenous administration of bortezomib at a low dose (1 mg/kg body weight) in wild-type or tumor-bearing mice altered the expression of a number of miRNAs in CD8+ T cells. Specifically, the effect of bortezomib was prominent on miR-155 - a key cellular miRNA involved in T cell function. Importantly, bortezomib–induced upregulation of miR-155 was associated with the downregulation of its targets, the suppressor of cytokine signaling 1 (SOCS1) and inositol polyphosphate-5-phosphatase (SHIP1). Genetic and biochemical analysis confirmed a functional link between miR-155 and these targets. Moreover, activated CD8+ T cells treated with bortezomib exhibited a significant reduction in programmed cell death-1 (PD-1) expressing SHIP1+ phenotype. These data underscore a mechanism of action by which bortezomib induces miR-155–dependent downregulation of SOCS1 and SHIP1 negative regulatory proteins, leading to a suppressed PD-1–mediated T cell exhaustion. Collectively, data provide novel molecular insights into bortezomib–mediated lymphocyte–stimulatory effects that could overcome immunosuppressive actions of tumor on antitumor T cell functions. The findings support the approach that bortezomib combined with other immunotherapies would lead to improved therapeutic outcomes by overcoming T cell exhaustion in the tumor microenvironment.

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