Reversing Tumor Immune Suppression with Intratumoral IL-12: Activation of Tumor-Associated T Effector/Memory Cells, Induction of T Suppressor Apoptosis, and Infiltration of CD8+T Effectors

Specific immune-cell populations patrol the CNS in search of pathogens and tumours. Herich et al. identify CD4+ CCR5high GzmK+ effector-memory cells as a brain-surveilling subpopulation capable of crossing the uninflamed blood-brain barrier, and reveal alterations in this population in HIV+ patients with neurological symptoms and in patients with multiple sclerosis.

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Index of Bone Marrow Output and Imbalance of B-Lymphocyte Homeostasis before and after Transplantation Correlate Differently with Graft-Versus-Host Disease and Relapse

Blood ◽

10.1182/blood.v126.23.3150.3150 ◽

2015 ◽

Vol 126 (23) ◽

pp. 3150-3150

Author(s):

Crisitina Skert ◽

Simone Perucca ◽

Imberti Luisa ◽

Chiarini Marco ◽

Michele Malagola ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

B Cells ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Effector Memory ◽

Memory Cells ◽

Immunological Parameters ◽

Immature B Cells ◽

Effector Memory Cells

Abstract Introduction The long-term efficacy of allogeneic haematopoietic stem cell transplantation (SCT) relies primarily on the Graft-versus-tumor (GVT) effect, which partially overlaps with Graft versus Host disease (GvHD), the most common cause of morbidity and mortality in SCT. Researches on GVHD-biomarkers are still ongoing and a set of validate markers are still lacking, especially for chronic GVHD. Furthermore, immune parameters that univocally associate with GVHD or GVT have not been identified yet. In this study, lymphocyte subsets together with TCR-repertoire analysis, and index of thymic and bone marrow output were evaluated at different time points, in order to identify possible predictors of GVHD and ineffective GVT. Methods Prospective evaluations of lymphocyte subsets, thymic and bone marrow output were performed in 40 patients before SCT, at 30, 90, 180 days and 1 year after SCT. CD4+/CD8+ naïve, central memory, effector memory, terminally differentiated effector memory (TEMRA) cells, subsets of regulatory T-lymphocytes, immature B cells, naïve, switched and unswitched memory B cells, memory double negative (IgD-CD27-) B cells were analysed by flow cytometry. Analysis of thymic and bone marrow output was performed by detection of T cell receptor excision circles (TRECs) and kappa-deleting recombination circles (KRECs). TRECs and KRECs were simultaneously quantified by a duplex quantitative Real-Time PCR. Heteroduplex assay was used to perform TCR-repertoire analysis. A 2-step multivariate analysis was performed using principal component analysis (PCA) and Cox regression analysis, to solve the problem of the high number of variables (immunological, patients- and transplant related) in comparison with the relatively limited and heterogeneous pool of patients. Results Twenty patients developed acute GVHD (median time: 28 days, range 19-120). Chronic GVHD was observed in 9 patients (median time: 6 months, range 4-10). In multivariate analysis, acute GVHD correlated positively with pre-transplant percentage of CD4+ central memory cells, and with values of regulatory effector memory T-cells and CD4+TEMRA cell at day +30 (p=0,0006). Pre-transplant percentage of unswitched memory B cells was also associated with acute GVHD, whereas pre-transplant levels of KRECs were inversely correlated (p=0,0005). Chronic GVHD was associated with matched unrelated donor and with (p<0,05): -values of regulatory effector memory T-cells at +30, percentage of CD8+TEMRA cells at +90, values of immature B cells and levels of KRECs at +180 (positive correlation) -percentage of CD4+ central memory and CD8+ effector memory cells at +90 (negative correlation). The relapse rate (27%; median time: 5,5 months, range 3-12) was used as clinical index of ineffective GVT. The following cluster of immunological parameters at day +90 correlated positively with relapse: CD8+ effector memory cells, immature B cells, naïve, switched memory B cells, memory double negative (IgD-CD27-) B cells (p=0,006). Discussion Different clusters of immunological parameters at different time points were evidenced as predictors of GVHD and ineffective GVT, allowing a clear-cut distinction between these immunological reactions. Changes in pre- and post-transplant B-lymphopoietic microenvironment and specific imbalances in the subset of B-cells may be involved in acute and chronic GVHD development. The atypical association of regulatory T-cells with GVHD may be explained by the relative efficiency of different subsets of regulatory T-cells (naïve>effector memory), as shown in some experimental models. Increased values of CD8+ effector memory cells could be an early sign of ineffective GVL. Imbalance toward a lymphocyte B-response, and especially toward "senescent" memory (IgD-CD27-) B cells, could promote tolerance to tumor cells. The validation of these clusters of immunological parameters as specific early predictors of GVHD or GVT, even before SCT, could potentially allow the development of pre-emptive and targeted therapies. Disclosures No relevant conflicts of interest to declare.

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Increase of CD8+ T-effector memory cells in peripheral blood of patients with relapsing–remitting multiple sclerosis compared to healthy controls

Journal of Neuroimmunology ◽

10.1016/j.jneuroim.2006.09.008 ◽

2007 ◽

Vol 183 (1-2) ◽

pp. 168-174 ◽

Cited By ~ 31

Author(s):

K.F. Haegele ◽

C.A. Stueckle ◽

J.-P. Malin ◽

E. Sindern

Keyword(s):

Multiple Sclerosis ◽

Peripheral Blood ◽

Effector Memory ◽

Healthy Controls ◽

Memory Cells ◽

Relapsing Remitting ◽

Effector Memory Cells ◽

Remitting Multiple Sclerosis ◽

Relapsing Remitting Multiple Sclerosis

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Resident Th1-Like Effector Memory Cells in Pulmonary Recall Responses toMycobacterium tuberculosis

American Journal of Respiratory Cell and Molecular Biology ◽

10.1165/rcmb.2005-0060oc ◽

2005 ◽

Vol 33 (1) ◽

pp. 48-55 ◽

Cited By ~ 43

Author(s):

Jessica Walrath ◽

Lynn Zukowski ◽

Adriana Krywiak ◽

Richard F. Silver

Keyword(s):

Effector Memory ◽

Memory Cells ◽

Effector Memory Cells

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Lipopolysaccharide Increases Immune Activation and Alters T Cell Homeostasis in SHIVB’WHUChronically Infected Chinese Rhesus Macaque

Journal of Immunology Research ◽

10.1155/2015/202738 ◽

2015 ◽

Vol 2015 ◽

pp. 1-13

Author(s):

Gao-Hong Zhang ◽

Run-Dong Wu ◽

Hong-Yi Zheng ◽

Xiao-Liang Zhang ◽

Ming-Xu Zhang ◽

...

Keyword(s):

T Cells ◽

Immune Activation ◽

Rhesus Macaques ◽

Effector Memory ◽

Memory Cells ◽

T Cell Homeostasis ◽

Programmed Cell Death 1 ◽

Effector Memory Cells ◽

Lymphocyte Homeostasis ◽

Chinese Rhesus Macaques

Immune activation plays a significant role in the disease progression of HIV. Microbial products, especially bacterial lipopolysaccharide (LPS), contribute to immune activation. Increasing evidence indicates that T lymphocyte homeostasis disruptions are associated with immune activation. However, the mechanism by which LPS affects disruption of immune response is still not fully understood. Chronically SHIVB’WHU-infected Chinese rhesus macaques received 50 μg/kg body weight LPS in this study. LPS administration affected the virus/host equilibrium by elevating the levels of viral replication and activating T lymphocytes. LPS induced upregulation of CD8+naïve T cells and downregulated the number of CD4+and CD8+T effector memory cells. The downregulated effector memory cells are associated with a lower frequency of monofunctional and polyfunctional cells, and an upregulated programmed cell death-1 (PD-1) expression on CD4+and CD8+T cells was observed in monkeys after LPS stimulation. Our data provide new insights into the function of LPS in the immune activation in SHIV/HIV infection.

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Prostate Cancer: Early Detection and Assessing Clinical Risk Using Deep Machine Learning of High Dimensional Peripheral Blood Flow Cytometric Phenotyping Data

Frontiers in Immunology ◽

10.3389/fimmu.2021.786828 ◽

2021 ◽

Vol 12 ◽

Author(s):

Georgina Cosma ◽

Stéphanie E. McArdle ◽

Gemma A. Foulds ◽

Simon P. Hood ◽

Stephen Reeder ◽

...

Keyword(s):

Peripheral Blood ◽

Specific Antigen ◽

Effector Memory ◽

Memory Cells ◽

Prostate Disease ◽

Clinical Risk ◽

High Risk Disease ◽

Effector Memory Cells ◽

Benign Prostate ◽

Asymptomatic Men

Detecting the presence of prostate cancer (PCa) and distinguishing low- or intermediate-risk disease from high-risk disease early, and without the need for potentially unnecessary invasive biopsies remains a significant clinical challenge. The aim of this study is to determine whether the T and B cell phenotypic features which we have previously identified as being able to distinguish between benign prostate disease and PCa in asymptomatic men having Prostate-Specific Antigen (PSA) levels < 20 ng/ml can also be used to detect the presence and clinical risk of PCa in a larger cohort of patients whose PSA levels ranged between 3 and 2617 ng/ml. The peripheral blood of 130 asymptomatic men having elevated Prostate-Specific Antigen (PSA) levels was immune profiled using multiparametric whole blood flow cytometry. Of these men, 42 were subsequently diagnosed as having benign prostate disease and 88 as having PCa on biopsy-based evidence. We built a bidirectional Long Short-Term Memory Deep Neural Network (biLSTM) model for detecting the presence of PCa in men which combined the previously-identified phenotypic features (CD8+CD45RA-CD27-CD28- (CD8+ Effector Memory cells), CD4+CD45RA-CD27-CD28- (CD4+ Effector Memory cells), CD4+CD45RA+CD27-CD28- (CD4+ Terminally Differentiated Effector Memory Cells re-expressing CD45RA), CD3-CD19+ (B cells), CD3+CD56+CD8+CD4+ (NKT cells) with Age. The performance of the PCa presence ‘detection’ model was: Acc: 86.79 ( ± 0.10), Sensitivity: 82.78% (± 0.15); Specificity: 95.83% (± 0.11) on the test set (test set that was not used during training and validation); AUC: 89.31% (± 0.07), ORP-FPR: 7.50% (± 0.20), ORP-TPR: 84.44% (± 0.14). A second biLSTM ‘risk’ model combined the immunophenotypic features with PSA to predict whether a patient with PCa has high-risk disease (defined by the D’Amico Risk Classification) achieved the following: Acc: 94.90% (± 6.29), Sensitivity: 92% (± 21.39); Specificity: 96.11 (± 0.00); AUC: 94.06% (± 10.69), ORP-FPR: 3.89% (± 0.00), ORP-TPR: 92% (± 21.39). The ORP-FPR for predicting the presence of PCa when combining FC+PSA was lower than that of PSA alone. This study demonstrates that AI approaches based on peripheral blood phenotyping profiles can distinguish between benign prostate disease and PCa and predict clinical risk in asymptomatic men having elevated PSA levels.

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CD8+CD161+ T-Cells: Cytotoxic Memory Cells With High Therapeutic Potential

Frontiers in Immunology ◽

10.3389/fimmu.2020.613204 ◽

2021 ◽

Vol 11 ◽

Author(s):

Vanaja Konduri ◽

Damilola Oyewole-Said ◽

Jonathan Vazquez-Perez ◽

Scott A. Weldon ◽

Matthew M. Halpert ◽

...

Keyword(s):

Gene Expression ◽

T Cells ◽

Cell Function ◽

Nk Cell ◽

Therapeutic Potential ◽

Cell Subset ◽

Effector Memory ◽

Memory Cells ◽

Mait Cells ◽

Effector Memory Cells

NK1.1 and its human homolog CD161 are expressed on NK cells, subsets of CD4+ and CD8+ T cells, and NKT cells. While the expression of NK1.1 is thought to be inhibitory to NK cell function, it is reported to play both costimulatory and coinhibitory roles in T-cells. CD161 has been extensively studied and characterized on subsets of T-cells that are MR1-restricted, IL-17 producing CD4+ (TH17 MAIT cells) and CD8+ T cells (Tc17 cells). Non-MAIT, MR1-independent CD161-expressing T-cells also exist and are characterized as generally effector memory cells with a stem cell like phenotype. Gene expression analysis of this enigmatic subset indicates a significant enhancement in the expression of cytotoxic granzyme molecules and innate like stress receptors in CD8+NK1.1+/CD8+CD161+ cells in comparison to CD8+ cells that do not express NK1.1 or CD161. First identified and studied in the context of viral infection, the role of CD8+CD161+ T-cells, especially in the context of tumor immunology, is still poorly understood. In this review, the functional characteristics of the CD161-expressing CD8+ T cell subset with respect to gene expression profile, cytotoxicity, and tissue homing properties are discussed, and application of this subset to immune responses against infectious disease and cancer is considered.

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