Immunosuppressive milieu of high-risk localized prostate cancer.

344 Background: The immune factors that modulate the aggressiveness of localized treatment-naïve prostate cancer remain poorly understood. Methods: Fresh tumor and peripheral blood were collected at the time of radical prostatectomy in patients with localized prostate cancer. We evaluated the immune cell composition of 22 patient samples employing multi-parametric flow cytometry. Samples were grouped by histological grade into intermediate (INTPCA) and high-grade (HIGHPCA) prostate cancers based on standard NCCN criteria and immune cell abundances were quantified by mean +/- SEM. Statistical significance was assessed using the Mann-Whitney test. Results: INTPCA and HIGHPCA tumors harbored a similar increase in CD8+ T cells ( p < 0.0005 and p < 0.05, respectively) and CD11b+CD68-CD16+ myeloid-derived cells (p < 0.05) relative to the peripheral blood. Other cell types were similarly decreased in both INTPCA and HIGHPCA, including CD11b+CD68+CD14+ ( p < 0.005 and p < 0.05, respectively). By contrast, regulatory T cells were the only cell type in our analysis to be uniquely enriched in HIGHPCA rather than INTPCA ( p < 0.05). The most unique feature found in phenotypic profiling of the immune repertoire of HIGHPCA relative to INTPCA was an increase in the immune inhibitory receptor ligand, PD-L1, in the tumor associated macrophages (CD11b+CD68+CD14+) compared to the periphery (p < 0.05). Conclusions: Collectively, our findings reveal that HIGHPCA harbors a distinct immunological landscape. Although effector CD8+ T cells are preferentially expressed in the tumor, these are met with an increased proportion of regulatory T cells as well as PD-L1 expressing macrophages that contribute to the inert tumor microenvironment. These are key features of aggressive prostate cancer that may serve as potential biomarkers and therapeutic targets.

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Single-Cell Profiling of Kidney Transplant Recipients With Immunosuppressive Treatment Reveals the Dynamic Immune Characteristics

Frontiers in Immunology ◽

10.3389/fimmu.2021.639942 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yongguang Liu ◽

Xiaoyou Liu ◽

Song Zhou ◽

Ruiquan Xu ◽

Jianmin Hu ◽

...

Keyword(s):

T Cells ◽

Kidney Transplantation ◽

Cd8 T Cells ◽

Immune Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Immune Cell ◽

Immunosuppressive Agents ◽

Cell Types ◽

Before And After

Kidney transplantation is currently the first choice of treatment for various types of end-stage renal failure, but there are major limitations in the application of immunosuppressive protocols after kidney transplantation. When the dose of immunosuppressant is too low, graft rejection occurs easily, while a dose that is too high can lead to graft loss. Therefore, it is very important to explore the immune status of patients receiving immunosuppressive agents after kidney transplantation. To compare the immune status of the recipient’s whole peripheral blood before and after receipt of immunosuppressive agents, we used single-cell cytometry by time-of-flight (CyTOF) to detect the peripheral blood immune cells in five kidney transplant recipients (KTRs) from the Department of Organ Transplantation of Zhujiang Hospital of Southern Medical University before and after receiving immunosuppressive agents. Based on CyTOF analysis, we detected 363,342 live single immune cells. We found that the immune cell types of the KTRs before and after receipt of immunosuppressive agents were mainly divided into CD4+ T cells, CD8+ T cells, B cells, NK cells/γδ T cells, monocytes/macrophages, granulocytes, and dendritic cells (DCs). After further reclustering of the above cell types, it was found that the immune cell subclusters in the peripheral blood of patients underwent major changes after receipt of immunosuppressants. After receiving immunosuppressive therapy, the peripheral blood of KTRs had significantly increased levels of CD57+NK cells and significantly decreased levels of central memory CD4+ T cells, follicular helper CD4+ T cells, effector CD8+ T cells, effector memory CD8+ T cells and naive CD8+ T cells. This study used CyTOF to classify immune cells in the peripheral blood of KTRs before and after immunosuppressive treatment, further compared differences in the proportions of the main immune cell types and immune cell subgroups before and after receipt of immunosuppressants, and provided relatively accurate information for assessment and treatment strategies for KTRs.

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Analysis of Regulatory T-cells-specific mRNAs for Improving Prognosis, Immunotherapy Response and Therapeutic Resistance of Patients With Prostate Cancer

10.21203/rs.3.rs-676662/v1 ◽

2021 ◽

Author(s):

Mingyi Ju ◽

Jingyi Fan ◽

Yuanjiang Zou ◽

Mingjie Yu ◽

Longyang Jiang ◽

...

Keyword(s):

Prostate Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Cancer Patients ◽

Tumor Immunity ◽

Immune Cell ◽

Cell Types ◽

Therapeutic Resistance ◽

Prognostic Signature ◽

Specific Mrnas

Abstract Background: Prostate cancer recognized as a “cold” tumor has an immunosuppressive microenvironment in which regulatory T-cells (Tregs) usually represent a major role. Therefore, identifying a prognostic signature of Tregs has promising benefits of improving survival of prostate cancer patients. However, the prognostic signature based on Tregs-specific mRNAs for prostate cancer is lacking. Methods: We systematicly analyzed transcriptional profiles of Tregs and 19 other immune cell types using 42 purified immune cell datasets from GEO to identify Tregs-specific mRNAs, and develop and validate a prognostic signature of Tregs (named “TILTregSig”) for monitoring prognosis of prostate cancer using TCGA and ICGC datasets. We also applied the signature to five immunotherapy response datasets and GSCALite to analyze the potential of the TILTregSig for predicting CIT response and cancer therapeutic resistance.Results: We develop the TILTregSig comprising five mRNAs (SOCS2, EGR1, RRM2, TPP1 and C11orf54) for prostate cancer patients. We find that the TILTregSig is a stronger predictor for tumor immunity compared with tumor mutation burden (TMB) and glycolytic activity which have been reported as immune predictors. Further analyses indicate that the TILTregSig may influence tumor immunity mainly by mediating tumor-infiltrating Tregs. Moreover, the TILTregSig also shows promising potential for predicting cancer immunotherapy (CIT) response and therapeutic resistance in multiple cancers.Conclusions: Our study has highlighted the value of the TILTregSig as a prognostic biomarker of prostate cancer from a tumor-infiltrating Tregs perspective, and strengthened its potential application as predictor of CIT response and cancer therapeutic resistance, which warrants further.

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Immunopathological characteristics of coronavirus disease 2019 cases in Guangzhou, China

10.1101/2020.03.12.20034736 ◽

2020 ◽

Cited By ~ 24

Author(s):

Yaling Shi ◽

Mingkai Tan ◽

Xing Chen ◽

Yanxia Liu ◽

Jide Huang ◽

...

Keyword(s):

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Hospital Stay ◽

Nk Cells ◽

Cd8 T Cells ◽

Immune Cell ◽

Length Of Hospital Stay ◽

Cell Types ◽

Respiratory Disorder

SummaryCoronavirus disease 2019 (COVID-19) is a respiratory disorder caused by the highly contagious SARS-CoV-2. The immunopathological characteristics of COVID-19 patients, either systemic or local, have not been thoroughly studied. In the present study, we analyzed both the changes in the cellularity of various immune cell types as well as cytokines important for immune reactions and inflammation. Our data indicate that patients with severe COVID-19 exhibited an overall decline of lymphocytes including CD4+ and CD8+ T cells, B cells, and NK cells. The number of immunosuppressive regulatory T cells was moderately increased in patients with mild COVID-19. IL-2, IL-6, and IL-10 were remarkably up-regulated in patients with severe COVID-19. The levels of IL-2 and IL-6 relative to the length of hospital stay underwent a similar “rise-decline”pattern, probably reflecting the therapeutic effect. In conclusion, our study shows that the comprehensive decrease of lymphocytes, and the elevation of IL-2 and IL-6 are reliable indicators of severe COVID-19.

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Anti-Thymocyte Globulin (ATG) Differentially Depletes naïve and Memory T Cells and Permits Memory-Type Regulatory T Cells

Blood ◽

10.1182/blood.v120.21.4670.4670 ◽

2012 ◽

Vol 120 (21) ◽

pp. 4670-4670

Author(s):

Chang-Qing Xia ◽

Anna Chernatynskaya ◽

Clive Wasserfall ◽

Benjamin Looney ◽

Suigui Wan ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Memory T Cells ◽

Conflicts Of Interest ◽

T Cell Subsets ◽

Hematopoietic Stem

Abstract Abstract 4670 Anti-thymocyte globulin (ATG) has been used in clinic for the treatment of allograft rejection and autoimmune diseases. However, its mechanism of action is not fully understood. To our knowledge, how ATG therapy affects naïve and memory T cells has not been well investigated. In this study, we have employed nonobese diabetic mouse model to investigate how administration of anti-thymocyte globulin (ATG) affects memory and naïve T cells as well as CD4+CD25+Foxp3+ regulatory T cells in peripheral blood and lymphoid organs; We also investigate how ATG therapy affects antigen-experienced T cells. Kinetic studies of peripheral blood CD4+ and CD8+ T cells post-ATG therapy shows that both populations decline to their lowest levels at day 3, while CD4+ T cells return to normal levels more rapidly than CD8+ T cells. We find that ATG therapy fails to eliminate antigen-primed T cells, which is consistent with the results that ATG therapy preferentially depletes naïve T cells relative to memory T cells. CD4+ T cell responses post-ATG therapy skew to T helper type 2 (Th2) and IL-10-producing T regulatory type 1 (Tr1) cells. Intriguingly, Foxp3+ regulatory T cells (Tregs) are less sensitive to ATG depletion and remain at higher levels following in vivo recovery compared to controls. Of note, the frequency of Foxp3+ Tregs with memory-like immunophenotype is significantly increased in ATG-treated animals, which might play an important role in controlling effector T cells post ATG therapy. In summary, ATG therapy may modulate antigen-specific immune responses through modulation of naïve and memory T cell pools and more importantly through driving T cell subsets with regulatory activities. This study provides important data for guiding ATG therapy in allogenieic hematopoietic stem cell transplantation and other immune-mediated disorders. Disclosures: No relevant conflicts of interest to declare.

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Single-Cell Sequencing of Mouse Heart Immune Infiltrate in Pressure Overload–Driven Heart Failure Reveals Extent of Immune Activation

Circulation ◽

10.1161/circulationaha.119.041694 ◽

2019 ◽

Vol 140 (25) ◽

pp. 2089-2107 ◽

Cited By ~ 30

Author(s):

Elisa Martini ◽

Paolo Kunderfranco ◽

Clelia Peano ◽

Pierluigi Carullo ◽

Marco Cremonesi ◽

...

Keyword(s):

Heart Failure ◽

T Cells ◽

Mast Cells ◽

Natural Killer Cells ◽

Regulatory T Cells ◽

Natural Killer ◽

Immune Activation ◽

Immune Cell ◽

Pressure Overload ◽

Cell Types

Background: Inflammation is a key component of cardiac disease, with macrophages and T lymphocytes mediating essential roles in the progression to heart failure. Nonetheless, little insight exists on other immune subsets involved in the cardiotoxic response. Methods: Here, we used single-cell RNA sequencing to map the cardiac immune composition in the standard murine nonischemic, pressure-overload heart failure model. By focusing our analysis on CD45 + cells, we obtained a higher resolution identification of the immune cell subsets in the heart, at early and late stages of disease and in controls. We then integrated our findings using multiparameter flow cytometry, immunohistochemistry, and tissue clarification immunofluorescence in mouse and human. Results: We found that most major immune cell subpopulations, including macrophages, B cells, T cells and regulatory T cells, dendritic cells, Natural Killer cells, neutrophils, and mast cells are present in both healthy and diseased hearts. Most cell subsets are found within the myocardium, whereas mast cells are found also in the epicardium. Upon induction of pressure overload, immune activation occurs across the entire range of immune cell types. Activation led to upregulation of key subset-specific molecules, such as oncostatin M in proinflammatory macrophages and PD-1 in regulatory T cells, that may help explain clinical findings such as the refractivity of patients with heart failure to anti–tumor necrosis factor therapy and cardiac toxicity during anti–PD-1 cancer immunotherapy, respectively. Conclusions: Despite the absence of infectious agents or an autoimmune trigger, induction of disease leads to immune activation that involves far more cell types than previously thought, including neutrophils, B cells, Natural Killer cells, and mast cells. This opens up the field of cardioimmunology to further investigation by using toolkits that have already been developed to study the aforementioned immune subsets. The subset-specific molecules that mediate their activation may thus become useful targets for the diagnostics or therapy of heart failure.

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Activation of DR3 Signaling Expands Recipient Derived Regulatory T Cells and Enhances Donor Immune Reconstitution Derived from Allogeneic Hematopoietic Stem Cells

Blood ◽

10.1182/blood.v124.21.1087.1087 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1087-1087

Author(s):

Hidekazu Nishikii ◽

Byung Su Kim ◽

Antonio Pierini ◽

Jeanette Baker ◽

Dominik Schneidawind ◽

...

Keyword(s):

Stem Cells ◽

T Cells ◽

B Cells ◽

Regulatory T Cells ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Cd4 T Cells ◽

Immune Reconstitution ◽

Hematopoietic Stem ◽

Hsc Transplantation

Abstract CD4+ Foxp3+ regulatory T cells (Treg) are a subpopulation of T cells which regulate the immune system, maintain the tolerance of self-antigens and enhance immune tolerance after transplantation. It was also reported that recipient derived Treg could provide immune privilege to allogeneic stem cells (HSC) after transplantation. However, the precise interaction with Treg and HSC has not been fully elucidated. In this study, we investigated the role of recipient derived Treg in the engraftment and immune reconstitution following transplantation of purified allogeneic HSC and the effectiveness of Treg expansion following activation of DR3 (Death receptor 3, also called as TNFRSF25) signaling in this model. 　We first tested the effect of Treg depletion using Foxp3-DTR mice in allogeneic HSC transplantation. In this system, FACS-sorted purified HSC (Lin-cKit+Sca1+ population) derived from WT-FVB mice (CD45.1+/H2kq+) were injected into lethally irradiated B6-Foxp3-DTR mice (CD45.2+/H2kb+) with or without pre-treatment of diphtheria toxin (DT). On day 0 and day 28 after transplantation decreased frequencies of Foxp3+ cells in residual recipient derived CD4+ T cells were observed in peripheral blood from the DT treated mice (P<0.001 on day 0, P<0.002 on day 28). Although total myeloid chimerism was comparable between control and DT-treated mice, the frequency of donor derived immune cells including CD4+ T cells (P<0.01 on day 56), CD8+ T cells (P<0.01 on day 56), and B220+ B cells (P<0.001 on day 56) was significantly decreased in DT-treated mice. These data suggested that recipient derived Treg play an important role in allogeneic immune reconstitution after transplantation. DR3 is a member of the TNF receptor superfamily and we previously reported the expansion of Treg by the activation of this signaling pathway (Kim et al, ASH abstract 2013). We next tested whether activation of DR3 signaling by its agonistic antibody would affect the donor immune reconstitution after allogeneic HSC transplantation. The frequencies of Foxp3+ cells in CD4+ T cells were significantly increased in thymus, spleen, peripheral blood, and bone marrow 4 days after antibody injection (P<0.01). Isolated Treg derived from antibody treated mice showed stronger suppressive function in the mixed lymphoid reaction compared with those from isotype antibody treated mice. The mice treated with antibody on day -4 were transplanted with purified allogeneic HSC on day 0. Antibody treated mice showed a higher frequency of donor derived CD4+ T cells (P<0.001 on day 28), CD8+ T cells (P<0.05 on day 28), and B220+ B cells (P<0.05 on day 28) in this allogeneic HSC transplantation model. In summary, our data suggest that recipient derived CD4+Foxp3+ Treg play an important role in donor immune reconstitution and the activation of DR3 signaling in recipient mice enhances donor immune reconstitution by expansion of recipient derived Treg. H.N and BS-K contributed equally to this work. Disclosures No relevant conflicts of interest to declare.

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Frequency of CD4+ regulatory T cells, CD8+ T cells, and human papilloma virus infection in Egyptian Women with breast cancer

International Journal of Immunopathology and Pharmacology ◽

10.1177/2058738420966822 ◽

2020 ◽

Vol 34 ◽

pp. 205873842096682

Author(s):

Amany M Tawfeik ◽

Ahmed Mora ◽

Ahmed Osman ◽

Manar M Moneer ◽

Nabila El-Sheikh ◽

...

Keyword(s):

Breast Cancer ◽

T Cells ◽

Regulatory T Cells ◽

Human Papilloma Virus ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Early Stage ◽

Hpv Infection ◽

Papilloma Virus ◽

Egyptian Women

Several subsets of regulatory CD4+ T cells (CD4+ Tregs) have been described in peripheral blood and tumor microenvironment of breast cancer (BC) patients and may play a role in the progression of BC. High-risk human papilloma virus (HR-HPV) has a causal role in cervical, head, and neck tumors but the role of HR-HPV in evoking neoplasia in BC is still unclear. In this study we assessed the prevalence of CD4+CD25+ FOXP3+ regulatory T cells (CD4+Tregs) and CD3+ CD8+ T cells by flow cytometry in peripheral blood from a total of 55 Egyptian women, including 20 treatment-naïve BC, 15 with breast benign lesions (BBL), and 20 healthy volunteers (HV). HR-HPV genotypes type 16, 18, and 31 were investigated in breast tissue from all BC and BBL patients using Real-Time PCR. HR-HPV was detected in 4/20 (20%) and 0/15 (0%) BC and BBL patients respectively. The frequency of CD4+ Tregs was significantly higher in BC compared to BBL and HV, ( P < 0.001). In addition, we observed a significantly higher frequency of CD3+ CD8+ T cells in peripheral blood of patients with late stage III BC compared to early stage I and II BC ( P = 0.011). However, there was no significant association between the ratio of CD8+ T cell to CD4+ Tregs frequencies and the expression of Estrogen Receptor (ER), Progesterone Receptor (PR), and Human Epidermal Growth Factor Receptor 2 (HER2). These results lead us to postulate that the association between the frequency of CD4+ Tregs and CD8+ T cells in the peripheral blood may be a prognostic or predictive parameter in Egyptian women with BC. In addition, HR-HPV infection may be implicated in the development of some types of BC in Egyptian women.

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Impact of the immune cell population in peripheral blood on response and survival in patients receiving neoadjuvant chemotherapy for advanced gastric cancer

Tumor Biology ◽

10.1177/1010428317697571 ◽

2017 ◽

Vol 39 (5) ◽

pp. 101042831769757 ◽

Cited By ~ 5

Author(s):

Qi He ◽

Guoli Li ◽

Xiang Ji ◽

Long Ma ◽

Xulin Wang ◽

...

Keyword(s):

Gastric Cancer ◽

T Cells ◽

Neoadjuvant Chemotherapy ◽

Clinical Outcome ◽

Advanced Gastric Cancer ◽

Cd8 T Cells ◽

Peripheral Blood ◽

Immune Cell ◽

T Cell Subsets ◽

Response To Chemotherapy

We aimed to investigate the prognostic value of the immune cells population in peripheral blood from patients with advanced gastric cancer treated with neoadjuvant chemotherapy. A total of 105 patients with advanced gastric cancer were evaluated in this study. Blood samples were collected before and 1 week after the last dose of chemotherapy. The percentage of CD3+, CD3+CD4+, CD3+CD8+, and CD4+CD25+Foxp3+ T cells was assessed using flow cytometry analysis. The relationship between T cell subsets and clinical outcome was evaluated. The percentage of CD3+CD8+ lymphocytes was significantly increased after chemotherapy and CD4+CD25+Foxp3+ regulatory T cells (Tregs) decreased ( p = 0.003 and p < 0.001, respectively). The percentage of CD3+CD8+ lymphocytes and Tregs was strongly associated with response to chemotherapy ( p = 0.017 and p < 0.030, respectively). Patients with high CD3+CD8+ T cells and low CD4+CD25+Foxp3+ Tregs had significantly increased overall survival ( p = 0.012 and p = 0.048, respectively). Neither CD3+ nor CD3+CD4+ T cells showed significant changes after chemotherapy or correlations with the clinical outcome. The positive correlation between a high CD3+CD8+ T cells or low CD4+CD25+Foxp3+ Tregs and clinical outcome indicates its key role in the prognosis of gastric cancer patients and may serve as a biomarker to identify patients likely to benefit from neoadjuvant chemotherapy.

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Leukocyte Counts and T Cell Frequencies Differ Between Novel Subgroups of Diabetes and Associate with Metabolic Parameters and Biomarkers of Inflammation

10.2337/figshare.15782064.v1 ◽

2021 ◽

Author(s):

Jacqueline M. Ratter-Rieck ◽

Haifa Maalmi ◽

Sandra Trenkamp ◽

Oana-Patricia Zaharia ◽

Wolfgang Rathmann ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

Regulatory T Cells ◽

Immune Cell ◽

Autoimmune Diabetes ◽

Cell Types ◽

Recent Onset ◽

Insulin Resistant ◽

Cell Counts ◽

Age Related

Frequencies of circulating immune cells are altered in type 1 and type 2 diabetes compared with healthy individuals and associate with insulin sensitivity, glycemic control and lipid levels. This study aimed to determine whether specific immune cell types are associated with novel diabetes subgroups. We analyzed automated white blood cell counts (n=669) and flow cytometry data (n=201) of participants of the German Diabetes Study with recent-onset (<1 year) diabetes, who were allocated to five subgroups based on data-driven analysis of clinical variables. Leukocyte numbers were highest in severe insulin-resistant diabetes (SIRD) and moderate obesity-related diabetes (MOD) and lowest in severe autoimmune diabetes (SAID). CD4+ T cell frequencies were higher in SIRD vs. SAID, MOD and mild age-related diabetes (MARD), and frequencies of CCR4+ regulatory T cells were higher in SIRD vs. SAID and MOD and MARD vs. SAID. Pairwise differences between subgroups were partially explained by differences in clustering variables. Frequencies of CD4+ T cells were positively associated with age, BMI, HOMA2-B and HOMA2-IR, and frequencies of CCR4+ regulatory T cells with age, HOMA2-B and HOMA2-IR. In conclusion, different leukocyte profiles exist between novel diabetes subgroups and suggest distinct inflammatory processes in these diabetes subgroups.

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