scholarly journals CXCL13 Correlates with Prognosis, Immune Infiltration, and T Cell Exhaustion in Ovarian Cancer

2021 ◽  
Author(s):  
Hailing Duan ◽  
Ying Lv ◽  
Pan Liao ◽  
Yiming Wang ◽  
Zhifang Zheng ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
T Cells ◽  
Cell Adhesion ◽  
T Cell ◽  
Immune Cells ◽  
Gene Marker ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Infiltration ◽  
Prognosis Prediction

Abstract Background: CXCL13 is an important chemotactic factor closely related to the biology of cancer cells. The presence work focused on exploring the significance of CXCL13 in prognosis prediction and analyzing the associations of CXCL13 with T cell function and immune infiltration in various cancers, especially ovarian cancer (OV).Purpose: CXCL13 is associated with prognosis, immune infiltration, and T cell failure of ovarian cancer.Methods: The Oncomine, GEPIA2 and HPA databases were utilized for analyzing CXCL13 levels within diverse cancers. The significance of CXCL13 in prognosis prediction was explored through Kaplan-Meier Plotter, TCGAportal, and GEPIA2. Meanwhile, the associations of CXCL13 with clinical stage, gene marker sets, and immune infiltration were examined through TISIDB, GEPIA2, and TIMER databases. Besides, CXCL13 was screened to analyze the biological processes (BPs) and KEGGs enriched by co-expression genes. The miRWalk database was employed for analyzing the gene-miRNA interaction network of CXCL13 within OV.Results: CXCL13 expression decreased in many cancers, which predicted the dismal survival of OV. CXCL13 upregulation was in direct proportion to the increased immune infiltration degrees of many functional T cells (like exhausted T cells) and immune cells. Additionally, some critical genes of exhausted T cells, such as TIM-3, PD-1, LAG3, TIGIT, GZMB, and CXCL13, were closely associated with CXCL13. Moreover, CXCL13 was related to immune response regulatory signaling pathway, leukocyte cell-cell adhesion, cell adhesion molecules (CAMs), and hematopoietic cell lineage. Conclusion: CXCL13 can serve as a biomarker to predict cancer prognosis, particularly OV. CXCL13 upregulation remarkably elevates the immune infiltration degrees of numerous immune cells, like mast cells, CD8+ T cells, natural killer (NK) cells, and dendritic cells (DCs). Furthermore, CXCL13 is suggested to be closely related to exhausted T cells, which may be used as a candidate regulating factor for T cell exhaustion within OV. Detecting CXCL13 levels contributes to prognosis prediction and CXCL13 regulation within exhausted T cells, which provides a new approach to maximizing the anti-OV efficacy of immunotherapy.

scholarly journals PLAC8 Correlates with Prognosis, Immune Infiltration, and T Cell Exhaustion in Breast Cancer

2021 ◽  
Author(s):  
Pan Liao ◽  
Ying Wang ◽  
Lixia Sun ◽  
Hongpeng Yue
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
T Cell ◽  
T Cell Activation ◽  
Prognostic Significance ◽  
Her2 Status ◽  
Gene Marker ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Infiltration

Abstract Background: Lysosomal protein placenta-specific 8 (PLAC8) with abundant cysteine, also referred to as onzin, participates in numerous cancers, and its effect is greatly determined by the cellular and tumor microenvironment (TME). Ourstudy focused on investigating the prognostic significance of PLAC8 and examined the association between PLAC8, immune infiltration, and T cells function in multiple malignancies comprehensively, particularly in breast cancer (BRCA).Methods: PLAC8 expression in various malignancies was analyzed using TIMER. PrognoScan, Kaplan-Meier Plotter, and GEPIA2 were utilized to explore the significance of PLAC8 in prognostic prediction. Moreover, PLAC8 functions were systematically analyzed through cancerSEA. Additionally, TISIDB, TIMER, and GEPIA2 were also employed for analyzing the associations among PLAC8, immune infiltration, related gene marker sets, and clinical stages. Finally, PLAC8 and its co-expressed genes biological process and KEGG were analyzed. Results: PLAC8 expression decreased in most malignancies and was related to poor prognosis in BRCA. PLAC8 significantly affected the survival of BRCA with ER status – array, PR status – IHC, HER2 status – array, Intrinsic subtype, Grade, and Pietenpol subtype. Increased PLAC8 expression positively correlated with the increased immune infiltration levels within immune cells and many functional T cells (such as exhausted T cells). In BRCA cells, PLAC8 functional phenotypesshowed a negative correlation with invasion, metastasis, apoptosis, DNA damage, and DNA repair. Besides, PD-1, TIM-3, TIGIT, LAG3, and GZMB, critical genes of exhausted T cells, interacted with PLAC8. Further analysis indicated that PLAC8 was related to T cell activation, proliferation and adhesion of leukocytes,adaptive immune response, cell adhesion molecules (CAMs), cytotoxicity-mediated by natural killer cells, and the NF-kappa B signal transduction pathway.Conclusion:PLAC8 is a prognostic indicator in pan-cancers, especially BRCA. Elevated PLAC8 level could significantly enhance immune infiltration in CD4+ T cells, CD8+ T cells, and functional T cells. Additionally, PLAC8 was tightly associatedwith T cell exhaustion which possibly enhances the latterwithin BRCA. PLAC8 expression determination might help in prognosis, and modulation of PLAC8level within exhausted T cells, a novel approach for optimizing the therapeutic effect of immunotherapy on BRCA cases.

scholarly journals Correlation of MKI67 with prognosis, immune infiltration, and T cell exhaustion in hepatocellular carcinoma

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Shi-yi Wu ◽  
Pan Liao ◽  
Lu-yu Yan ◽  
Qian-yi Zhao ◽  
Zhao-yu Xie ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Vital Role ◽  
Prediction Performance ◽  
Liver Carcinoma ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Infiltration ◽  
Prognosis Prediction ◽  
Prognostic Prediction

Abstract Background MKI67 plays a vital role in the tumour microenvironment (TME) and congenital immunity. The present work focuses on exploring the prognosis prediction performance of MKI67 and its associations with T cell activity and immune infiltration within numerous cancers, especially hepatocellular liver carcinoma (LIHC). Methods Oncomine, GEPIA2, and HPA were adopted to analyse MKI67 levels in different types of cancers. The prognostic prediction performance of MKI67 was evaluated through the TCGA portal, GEPIA2, LOGpc, and Kaplan–Meier Plotter databases. The associations of MKI67 with related gene marker sets and immune infiltration were inspected through TISIDB, GEPIA2, and TIMER. We chose MKI67 to analyse biological processes (BPs) and KEGG pathways related to the coexpressed genes. Furthermore, the gene–miRNA interaction network for MKI67 in liver cancer was also examined based on the miRWalk database. Results MKI67 expression decreased in many cancers related to the dismal prognostic outcome of LIHC. We found that MKI67 significantly affected the prognosis of LIHC in terms of histology and grade. Increased MKI67 levels were directly proportional to the increased immune infiltration degrees of numerous immune cells and functional T cells, such as exhausted T cells. In addition, several critical genes related to exhausted T cells, including TIM-3, TIGIT, PD-1, LAG3, and CXCL13, were strongly related to MKI67. Further analyses showed that MKI67 was associated with adaptive immunity, cell adhesion molecules (CAMs), and chemokine/immune response signal transduction pathways. Conclusion MKI67 acts as a prognostic prediction biomarker in several cancers, particularly LIHC. Upregulation of MKI67 elevates the degree of immune infiltration of many immune cell subtypes, including functional T cells, CD4+ T cells, and CD8+ T cells. Furthermore, MKI67 shows a close correlation with T cell exhaustion, which plays a vital role in promoting T cell exhaustion within LIHC. Detection of the MKI67 level contributes to prognosis prediction and MKI67 modulation within exhausted T cells, thus providing a new method to optimize the efficacy of anti-LIHC immunotherapy.

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 T-Cell Exhaustion Status Under High and Low Levels of Hypoxia-Inducible Factor 1α Expression in Glioma

2021 ◽  
Vol 12 ◽  
Author(s):  
Shuai Liu ◽  
Xing Liu ◽  
Chuanbao Zhang ◽  
Wei Shan ◽  
Xiaoguang Qiu
Keyword(s):  
T Cells ◽  
T Cell ◽  
Immune Cells ◽  
Hypoxia Inducible Factor ◽  
Lower Grade ◽  
T Cell Exhaustion ◽  
Expression Levels ◽  
Cell Exhaustion ◽  
Lower Grade Glioma ◽  
Genome Atlas

Background: Hypoxia-inducible factor 1α (HIF1A), the principal regulator of hypoxia, is involved in the suppression of antitumor immunity. We aimed to describe the T-cell exhaustion status of gliomas under different levels of HIF1A expression.Methods: In this study, 692 patients, whose data were collected from the Chinese Glioma Genome Atlas (CGGA) database, and 669 patients, whose data were collected from The Cancer Genome Atlas database, were enrolled. We further screened the data of a cohort of paired primary and recurrent patients from the CGGA dataset (n = 50). The abundance of immune cells was calculated using the transcriptome data. The association between HIF1A and T-cell exhaustion-related genes and immune cells was investigated.Results: According to the median value of HIF1A expression, gliomas were classified into low-HIF1A-expression and high-HIF1A-expression groups. The expression levels of PDL1 (CD274), FOXO1, and PRDM1 in the high-HIF1A-expression group were significantly higher in both glioblastoma (GBM) and lower-grade glioma. The abundance of exhausted T cells and B cells was significantly higher in the high-HIF1A-expression group, while that of macrophage, monocyte, and natural killer cell was significantly higher in the low-HIF1A-expression group in both GBM and lower-grade glioma. After tumor recurrence, the expression of HIF1A significantly increased, and the correlation between HIF1A expression levels and exhausted T cells and induced regulatory T cells became stronger.Conclusion: In diffuse gliomas, the levels of T-cell exhaustion-associated genes and the abundance of immune cells were elevated under high HIF1A expression. Reversing hypoxia may improve the efficacy of immunotherapy.

Examining the Heterogeneity of Follicular Lymphoma By Multi-Parameter Flow Cyotmetry in Previously Untreated Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 2947-2947
Author(s):  
Debra K Czerwinski ◽  
Steven R Long ◽  
Michael Khodadoust ◽  
Matthew J. Frank ◽  
Adel Kardosh ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Tumor Cells ◽  
Immune Cells ◽  
Research Funding ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Abstract BACKGROUND: Follicular lymphoma (FL) is an indolent form of Non-Hodgkin B cell lymphoma that remains incurable with present therapies. Derived from germinal center B cells, FL B cells experience ongoing hypermutation of the immunoglobulin variable region gene. In addition, Michael Green, et al (PNAS; 2015), reported the presence of numerous somatic mutations to include those of the chromatin-modifying genes. These mutations accumulate over the course of the disease and play an important role in regulating gene transcription, B cell development and immune interactions. Furthermore, FL tumors maintain a resemblance to primary lymphoid follicles, and as such, present with a number of infiltrating immune cells, especially T cells, the numbers of which vary from patient to patient. The close association and interaction of these immune cells with the tumor B cells play an important part in determining the disease biology (Dave SS, et al. N Engl J Med; 2004). For instance, tumor B cells, through cell-cell contact with these immune cells and/or through secretion of inhibitory cytokines such as TGF-b and IL-10, induce T cell exhaustion and apoptosis as well as suppressive T cell phenotypes (FoxP3+ T Regulatory cells) thus evading immune eradication (Yang Z-Z, et al. Blood 2007 and Ai WZ, et al. IntJ Cancer; 2009). They also promote their own survival and proliferation through their interaction with resident T follicular helper cells via CD40L/CD40 interactions (Ame'-Thomas P, et al. Blood; 2005). As a corollary to an ongoing clinical trial, we received fine needle aspirates (FNAs) of easily accessible tumors from 14 patients with FL prior to any treatment. 6 of these patients had samples taken from a second site simultaneously. All samples were processed within 24 hours into a single-cell suspension; red blood cells were lysed. Cells were then stained with antibodies to delineate T, B, NK, dendritic, and myeloid cells, as well as their subsets. Antibodies against activation antigens, T cell exhaustion, inhibition and function were also used to characterize these cells. Finally, the cells were run on a 17-parameter LSRII (Becton Dickinson) and data analyzed via Cytobank, a web-based data storage and analysis tool. PURPOSE: To better understand the biology of FL as represented by protein expression by the tumor cells and the immune cells that make up the microenvironment. We will especially look to evaluate the heterogeneity inherent in FL by flow cytometry across patients as well as within any one individual. RESULTS: Each sample is stained with 4 panels of antibodies, 13 antibodies each, allowing us to measure over 100 cell subsets. A quick preview of all data shows that there is a high variability between patients in the percentage of T cells within the microenvironment (37.7% + 16.6% of all cells collected from all samples). This variability is represented by the differences in the CD4 T cell compartment (27.6 + 12.9%) and to a lesser degree in the CD8 compartment (7.7 + 3.7%). To note, this variability in T cells does not correlate with time from diagnosis to sample collection which ranged from 3.4 years to approximately 5 months. Also, this is in contrast to the similar percentage of CD4 and CD8 T cells expressing PD-1 (55.5 + 8.8% and 46.0 + 8.9%, respectively) across patients. Notably, there is much less variability from site to site within each patient then between patients as demonstrated by Figure 1 where Site A and Site B are 2 separate lesions within each patient listed, sampled at the same time. Since FL presumably begins in a single site in the body and then becomes disseminated, the fact that a characteristic relationship exists between tumor cells and immune cells wherever the disease is found implies a mutual interdependence of the tumor cells in each case and their immune host component. CONCLUSION: Follicular lymphoma is a very heterogeneous disease as would be expected by the diversity of mutations seen at the genomic level. This heterogeneity is also apparent in the microenvironment from one patient to another. Conversely, different tumor sites within each patient have a characteristic and fixed relationship to their immune microenvironment. The emergence of novel therapies for FL, including checkpoint antibodies such as anti-PD-1 and anti-PD-L1 and small molecules such as Ibrutinib, will be informed by understanding the differences as well as the similarities in each case of FL. Disclosures Levy: Kite Pharma: Consultancy; Five Prime Therapeutics: Consultancy; Innate Pharma: Consultancy; Beigene: Consultancy; Corvus: Consultancy; Dynavax: Research Funding; Pharmacyclics: Research Funding.

scholarly journals Disruption of TET2 Dioxygenase Enhances Antitumor Efficiency in CD8+ Tumor Infiltrating Lymphocytes

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 860-860 ◽  
Author(s):  
Minjung Lee ◽  
Hongxiang Zeng ◽  
Jia Li ◽  
Wei Han ◽  
Deqiang Sun ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Cancer Therapy ◽  
Cd8 T Cells ◽  
Immune Cells ◽  
Tumor Infiltrating Lymphocytes ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Melanoma Progression ◽  
Infiltrating Lymphocytes

Abstract Background: T cell exhaustion is a dysfunctional state of T cell that occurs during many chronic infections and cancer [1,2]. T cell exhaustion is generally defined by poor effector function, continuous expression of inhibitory receptors and a distinctive transcriptional state when compared with functional effector T cells [2]. Exhaustion prevents optimal control of infection and tumors. Recently, a clearer picture of the functional and phenotypic profiles of exhausted T cells has emerged and T cell exhaustion has been defined in many experimental and clinical settings. Although the involved pathways remain to be fully defined, advances in the molecular delineation of T cell exhaustion are clarifying the underlying causes of this state of differentiation and also suggest promising therapeutic opportunities. A recent study reported disruption of TET2 to promote the therapeutic efficacy of CD19 targeted T cells during cancer immunotherapy [3]. Furthermore, Tet2 deficient macrophages could alter the tumor microenvironment to reduce tumor burden during melanoma progression [4]. Together, these data suggest, contrary to the tacit belief of Tet2 as a tumor suppressor, deletion of Tet2 in specific subsets of immune cells might enhance anti-tumor immunity to benefit cancer therapy. In this study, we set out to explore the role of Tet2 in CD8+ tumor infiltrating lymphocytes (TIL) during melanoma progression. Methods: We intradermally injected B16-OVA mouse melanoma cell lines in B6.SJL-Ptprca Pepcb/BoyJ (CD45.1) mice, and use this as an in vivo model to monitor melanoma progression [5]. In parallel, we injected WT-OTI and Tet2KO-OTI CD8+ T cells into CD45.1 mice injected with B16-OVA cells. Melanoma progression was monitored by measuring the tumor sizes for two weeks. At the end point, spleen and tumor infiltrated CD45.2+CD8+ cells were collected and analyzed. RNA-seq, ATAC-seq and CMS-IP-seq experiments were carried out to examine genome-wide gene expression, chromatin accessibility and DNA hydroxymethylation, with the goal of unveiling the underlying molecular mechanisms. Results: Compared with the control mice injected with WT-OTI CD8+ T cells, we observed a strong delay of melanoma disease progression and up to 80% reduction in tumor sizes in mice injected with Tet2KO-OTI CD8+ T cells. Flow cytometry analysis showed no significant changes in CD8+ T cell populations in major lymphoid organs. However, we detected a pronounced reduction of T cell exhaustion in Tet2KO CD8+ TILs compared with the WT group. Further transcriptome and integrative epigenome analysis revealed that Tet2 deleted TILs showed augmented activation of immune related pathways and reduction of the expression of immunosuppressive genes. Conclusion: Our novel findings demonstrated the therapeutic potential of Tet2 inactivation in immune cells during cancer immunotherapy. In our study, we observed that Tet2 depleted CD8+ TILs displayed increased anti-tumor efficiency in a mouse model of melanoma. Tet2 deletion could effectively alleviate T cell exhaustion to boost CD8+ TIL function. Nonetheless, since Tet2 deficiency is closely associated with various hematology disorders [6,7]; cautions must be taken to balance the tumor promoting and immune-boosting properties of Tet2 during cancer therapy. A temporally controllable system to inactivate Tet2 in specific immune cells might be most desirable for pursuing future therapeutic intervention by targeting Tet2. References 1. Thommen, D. S. & Schumacher, T. N. (2018). Cancer Cell33, 547-562. 2. Wherry, E. J. (2011). Nat Immunol12, 492-499. 3. Fraietta, J. A., Nobles, C. L., Sammons, M. A.et al. (2018). Nature558, 307-312. 4. Pan, W., Zhu, S., Qu, K.et al. (2017). Immunity47, 284-297 e285. 5. Mognol, G. P., Spreafico, R., Wong, V.et al. (2017). Proc Natl Acad Sci U S A114, E2776-E2785. 6. Couronne, L., Bastard, C. & Bernard, O. A. (2012). N Engl J Med366, 95-96. 7. Delhommeau, F., Dupont, S., Della Valle, V.et al. (2009). N Engl J Med360, 2289-2301. Disclosures No relevant conflicts of interest to declare.

scholarly journals AGTRAP Is a Prognostic Biomarker Correlated With Immune Infiltration in Hepatocellular Carcinoma

2021 ◽  
Vol 11 ◽  
Author(s):  
Shanshan Liu ◽  
Wei Zhao ◽  
Xuemei Li ◽  
La Zhang ◽  
Yu Gao ◽  
...  
Keyword(s):  
Hepatocellular Carcinoma ◽  
T Cells ◽  
T Cell ◽  
Normal Liver ◽  
Mrna Levels ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Immune Infiltration ◽  
Protein Levels ◽  
Liver Tissues

BackgroundRecently, it has been reported that angiotensin II receptor-associated protein (AGTRAP) plays a substantial role in tumor progression. Nevertheless, the possible role of AGTRAP in hepatocellular carcinoma (HCC) remains unrecognized.MethodsThe metabolic gene rapid visualizer, Cancer Cell Line Encyclopedia, Human Protein Atlas, and Hepatocellular Carcinoma Database were used to analyze the expression of AGTRAP in HCC tissues and normal liver tissues or adjacent tissues. Kaplan-Meier plotter and UALCAN analysis were used to assess the prognostic and diagnostic value of AGTRAP. LinkedOmics and cBioPortal were used to explore the genes co-expressed with AGTRAP in HCC. To further understand the potential mechanism of AGTRAP in HCC, Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment pathway analyses were performed using R software, the protein-protein interaction (PPI) network was established using the STRING database, and the immune infiltration and T-cell exhaustion related to AGTRAP were explored via Timer and GEPIA. In addition, immunohistochemistry was used to detect the expression of AGTRAP protein in HCC tissues and paired adjacent tissues from clinical specimens.ResultsThis study found that the mRNA and protein levels of AGTRAP in HCC tissues were higher than those in normal liver tissues and adjacent tissues, and higher mRNA levels of AGTRAP were associated with higher histological grade and a poor overall survival in HCC patients. The area under the receiver operating characteristic curve (AUC) of AGTRAP was 0.856, suggesting that it could be a diagnostic marker for HCC. Moreover, the alteration rate of AGTRAP in HCC was 8%, and AGTRAP was involved in HCC probably through the NF-κB and MAPK signaling pathways. Furthermore, AGTRAP was positively correlated with the infiltration of CD8+ T cells, CD4+ T cells, B cells, macrophages, dendritic cells, and neutrophils, and the levels of AGTRAP were significantly correlated with T-cell exhaustion biomarkers. The immunohistochemistry results confirmed that the protein levels of AGTRAP were consistently higher in HCC tissues than in paired adjacent tissues.ConclusionThe clinical value of AGTRAP and its correlation with immune infiltration in HCC was effectively identified in clinical data from multiple recognized databases. These findings indicate that AGTRAP could serve as a potential biomarker in the treatment of HCC, thereby informing its prognosis, diagnosis, and even immunotherapy.

scholarly journals Tim-3 adaptor protein Bat3 is a molecular checkpoint of T cell terminal differentiation and exhaustion

2021 ◽  
Vol 7 (18) ◽  
pp. eabd2710
Author(s):  
Chen Zhu ◽  
Karen O. Dixon ◽  
Kathleen Newcomer ◽  
Guangxiang Gu ◽  
Sheng Xiao ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adaptor Protein ◽  
Transcriptional Analysis ◽  
T Cell Exhaustion ◽  
Cell Exhaustion ◽  
Cell Dysfunction ◽  
Autoreactive T Cell ◽  
Autoimmune Conditions ◽  
T Cell Dysfunction

T cell exhaustion has been associated with poor prognosis in persistent viral infection and cancer. Conversely, in the context of autoimmunity, T cell exhaustion has been favorably correlated with long-term clinical outcome. Understanding the development of exhaustion in autoimmune settings may provide underlying principles that can be exploited to quell autoreactive T cells. Here, we demonstrate that the adaptor molecule Bat3 acts as a molecular checkpoint of T cell exhaustion, with deficiency of Bat3 promoting a profound exhaustion phenotype, suppressing autoreactive T cell–mediated neuroinflammation. Mechanistically, Bat3 acts as a critical mTORC2 inhibitor to suppress Akt function. As a result, Bat3 deficiency leads to increased Akt activity and FoxO1 phosphorylation, indirectly promoting Prdm1 expression. Transcriptional analysis of Bat3−/− T cells revealed up-regulation of dysfunction-associated genes, concomitant with down-regulation of genes associated with T cell effector function, suggesting that absence of Bat3 can trigger T cell dysfunction even under highly proinflammatory autoimmune conditions.

scholarly journals Partial restoration of immune response in Hepatitis C patients after viral clearance by direct-acting antiviral therapy

PLoS ONE ◽  
2021 ◽  
Vol 16 (7) ◽  
pp. e0254243
Author(s):  
Meritxell Llorens-Revull ◽  
Maria Isabel Costafreda ◽  
Angie Rico ◽  
Mercedes Guerrero-Murillo ◽  
Maria Eugenia Soria ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Hepatitis C ◽  
T Cell ◽  
Cd8 T Cells ◽  
Viral Clearance ◽  
Cd4 T Cell ◽  
Care Hospital ◽  
T Cell Exhaustion ◽  
Cell Exhaustion

Background & aims HCV CD4+ and CD8+ specific T cells responses are functionally impaired during chronic hepatitis C infection. DAAs therapies eradicate HCV infection in more than 95% of treated patients. However, the impact of HCV elimination on immune responses remain controversial. Here, we aimed to investigate whether HCV cure by DAAs could reverse the impaired immune response to HCV. Methods We analyzed 27 chronic HCV infected patients undergoing DAA treatment in tertiary care hospital, and we determined the phenotypical and functional changes in both HCV CD8+ and CD4+ specific T-cells before and after viral clearance. PD-1, TIM-3 and LAG-3 cell-surface expression was assessed by flow cytometry to determine CD4+ T cell exhaustion. Functional responses to HCV were analyzed by IFN-Ɣ ELISPOT, intracellular cytokine staining (IL-2 and IFN-Ɣ) and CFSE-based proliferation assays. Results We observed a significant decrease in the expression of PD-1 in CD4+ T-cells after 12 weeks of viral clearance in non-cirrhotic patients (p = 0.033) and in treatment-naive patients (p = 0.010), indicating a partial CD4 phenotype restoration. IFN-Ɣ and IL-2 cytokines production by HCV-specific CD4+ and CD8+ T cells remained impaired upon HCV eradication. Finally, a significant increase of the proliferation capacity of both HCV CD4+ and CD8+ specific T-cells was observed after HCV elimination by DAAs therapies. Conclusions Our results show that in chronically infected patients HCV elimination by DAA treatment lead to partial reversion of CD4+ T cell exhaustion. Moreover, proliferative capacity of HCV-specific CD4+ and CD8+ T cells is recovered after DAA’s therapies.

scholarly journals Exhausted CD8+T Cells in the Tumor Immune Microenvironment: New Pathways to Therapy

2021 ◽  
Vol 11 ◽  
Author(s):  
Weiqin Jiang ◽  
Yinjun He ◽  
Wenguang He ◽  
Guosheng Wu ◽  
Xile Zhou ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Burden ◽  
Effector Function ◽  
T Cell Exhaustion ◽  
Immune Microenvironment ◽  
Cell Exhaustion ◽  
Combination Strategies ◽  
Cell Pool ◽  
Tumor Immune Microenvironment

Tumor-specific CD8+T cells are exposed to persistent antigenic stimulation which induces a dysfunctional state called “exhaustion.” Though functioning to limit damage caused by immune response, T cell exhaustion leads to attenuated effector function whereby cytotoxic CD8+T cells fail to control tumor progression in the late stage. This pathway is a dynamic process from activation to “progenitor exhaustion” through to “terminally exhaustion” with distinct properties. With the rapid development of immunotherapy via enhancing T cell function, new studies are dissecting the mechanisms and identifying specific biomarkers of dynamic differentiation during the process of exhaustion. Further, although immune checkpoint inhibitors (ICIs) have achieved great success in clinical practice, most patients still show limited efficacy to ICIs. The expansion and differentiation of progenitor exhausted T cells explained the success of ICIs while the depletion of the progenitor T cell pool and the transient effector function of terminally exhausted T cells accounted for the failure of immune monotherapy in the context of exorbitant tumor burden. Thus, combination strategies are urgent to be utilized based on the reduction of tumor burden or the expansion of the progenitor T cell pool. In this review, we aim to introduce the concept of homeostasis of the activated and exhausted status of CD8+T cells in the tumor immune microenvironment, and present recent findings on dynamic differentiation process during T cell exhaustion and the implications for combination strategies in immune therapy.

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