Tumor-Infiltrating T Cells Are Not Predictive of Clinical Outcome in Follicular Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 824-824 ◽  
Author(s):  
Wei Yun Z. Ai ◽  
Debra Czerwinski ◽  
Sandra J. Horning ◽  
John Allen ◽  
Robert Tibshirani ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
Overall Survival ◽  
T Cells ◽  
Clinical Outcome ◽  
Follicular Lymphoma ◽  
Clinical Features ◽  
Training Set ◽  
Hla Dr ◽  
Validation Set

Abstract Background: Follicular lymphoma (FL) has variable clinical outcomes. It has been suspected that tumor-infiltrating immune cells affect the biology and outcome of this disease. Using gene expression profiling and immunoperoxide tissue staining techniques, T cells and macrophages have been related to the survival outcome in some studies, but not others. In the current study, we used flow cytometry to analyze T cells and their subsets in follicular lymphoma biopsy specimens and determined whether these cell populations correlated with clinical features and outcomes. Methods: Two hundred and eighty-nine follicular lymphoma patients (pt) presented from 1997 to 2003 underwent an excisional lymph node biopsy prior to any treatment. The median age of pt at diagnosis was 45.7 yrs, median follow-up was 8.6 yrs for living pts, and median survival was 15.7 yrs. All but 8 patients had stage III/IV disease, 5 had stage I/II, and 3 were unknown. The histological grades were: 162 (56%) grade 1, 112 (39%) grade 2, 13 (4.5%) grade 3 and 2 (0.5%) unknown. Among the 289 patients, 41(17%) had low FLIPI score, 150 (63%) intermediate, 48 (20%) high and 50 unknown. All biopsies were analyzed for CD20, CD3, CD4, CD8 and HLA-DR expression by single-parameter flow cytometry. The 289 pts were divided into a training set of 147 and a validation set of 142, stratified by age and era of diagnosis. We used these two factors to stratify the pts because age at diagnosis is the most important prognostic factor for survival, and, in our data set, the era of diagnosis had an impact on survival and on the time from diagnosis to first treatment. For our analysis, we began with the training set and used the percentages of each immune cell population as a continuous variable in a univariate analysis in relation to clinical features and outcomes. We chose 8 phenotypic variables: CD20, CD3, CD4, CD8, HLA-DR, CD4/CD3 ratio, CD8/CD3 ratio, and activated T cells [defined as (HLA-DR-CD20)/CD3]. Five parameters were used as clinical endpoints: overall survival, FLIPI score at diagnosis, the time from diagnosis to first treatment (defined as the time from the first treatment to second treatment), response to CVP as the first treatment and the duration of the benefit from the first treatment (defined as the time interval between initiation of first treatment and initiation of second treatment). Results: The number of pt evaluable for each of the outcome parameters was as follows: 289 for time to first treatment and for overall survival, 239 for FLIPI scores, 164 for response to CVP and 129 for duration of the benefit from the first treatment., Of the 8 variables tested in the training set, only CD4/CD3 ratio and CD8/CD3 ratio were marginally significant for the survival endpoint, with p 0.034 and 0.088, respectively. None of the variables was significant for any of the other endpoints. A multivariate analysis yielded CD4/CD3 as the only significant predictor for survival. When CD4/CD3 was tested in the validation set, it yielded a p value of 0.48. Conclusion: We find no evidence that the percentage of tumor-infiltrating T cells or their subsets is predictive of clinical outcome in follicular lymphoma. Any gene expression signature involving T cells that does relate to clinical outcome could therefore be a property of the activity of the cells rather than a simple reflection of their numbers.

scholarly journals POS0859 DEEP PHENOTYPING OF DERMATOMYOSITIS BASED ON LIPID FERROPTOSIS-RELATED GENES BY MACHINE LEARNING

2021 ◽  
Vol 80 (Suppl 1) ◽  
pp. 684.1-684
Author(s):  
J. Q. Zhang ◽  
S. X. Zhang ◽  
R. Zhao ◽  
J. Qiao ◽  
M. T. Qiu ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
Expression Profiles ◽  
Inflammatory Myopathy ◽  
Shanxi Province ◽  
Survival Prediction ◽  
Training Set ◽  
Redox Biology ◽  
Score Model ◽  
Validation Set

Background:Dermatomyositis (DM) is an idiopathic inflammatory myopathy with heterogeneous clinical manifestation that raise challenges regarding diagnosis and therapy1. Ferroptosis is a newly discovered form of regulated cell death that is the nexus between metabolism, redox biology, and rheumatic immune diseases2. However, how ferroptosis maintains the balance of lymphocyte T cells and affect disease activity in DM is unclear.Objectives:To investigate an ferroptosis-related multiple gene expression signature for classification by assessing the global gene expression profile, and calculate the lymphocyte T cells status in the different subsets.Methods:Gene expression profiles of skeletal muscle from DM samples were acquired from GEO database. GSE143323 (30 patients and 20 HCs) was selected as the training set. The GSE3307 contained 21 DM patients and was selected as the validation set. The 60 ferroptosis genes were obtained from previous literature3. The intersection of the global gene and ferroptosis genes was considered the set of significant G-Ferroptosis genes for further analysis. The “NMF” (R-package) was applied as an unsupervised clustering method for sample classification by using G-Ferroptosis genes expression microarray data from the training datasets. An ferroptosis score model was constructed. The performance of the ferroptosis genes-based risk score model constructed by the DM training set was validated in the batch-1 and batch-2 DM sets. Normalized ferroptosis genes training data was used to compare the ssGSEA scores of gene sets between the high risk and low risk group. The statistical software package R (version 4.0.3) was used for all analyses. P value < 0.05 were considered statistically significant.Results:We selected 54 significant G-Ferroptosis genes for further analysis in training set. There were 2 distinct subtypes (high-ferroptosis-score groups and low-ferroptosis-score groups) identified in G-Ferroptosis genes cohort which were also identified in validation datasets (Fig.1A, C, D). Metallothionein 1G (MT1G) was a characteristic gene of low-ferroptosis-score group. The characteristic genes of high-ferroptosis-score group were acyl-CoA synthetase family member 2(ACSF2) and aconitase 1(ACO1) (Fig.1B). Patients in high-ferroptosis-score group had a lower level of Tregs compared with that of low-ferroptosis-score patients in both training and validation set (P <0.05, Fig.1E).Conclusion:The biological process of ferroptosis is associated with the lever of Tregs, suggesting the process of ferroptosis may be involved in the disease progression of DM. Identificating ferroptosis-related features for DM might provide a new idea for clinical treatment.References:[1]DeWane ME, Waldman R, Lu J. Dermatomyositis: Clinical features and pathogenesis. Journal of the American Academy of Dermatology 2020;82(2):267-81. doi: 10.1016/j.jaad.2019.06.1309 [published Online First: 2019/07/08].[2]Liang C, Zhang X, Yang M, et al. Recent Progress in Ferroptosis Inducers for Cancer Therapy. Advanced materials (Deerfield Beach, Fla) 2019;31(51):e1904197. doi: 10.1002/adma.201904197 [published Online First: 2019/10/09].[3]Liang JY, Wang DS, Lin HC, et al. A Novel Ferroptosis-related Gene Signature for Overall Survival Prediction in Patients with Hepatocellular Carcinoma. International journal of biological sciences 2020;16(13):2430-41. doi: 10.7150/ijbs.45050 [published Online First: 2020/08/08].Acknowledgements:This project was supported by National Science Foundation of China (82001740).Open Fund from the Key Laboratory of Cellular Physiology (Shanxi Medical University) (KLCP2019) and Innovation Plan for Postgraduate Education in Shanxi Province (2020BY078).Disclosure of Interests:None declared

The Percentage of Tumor-Infiltrating T Cells Is Not Correlated with Overall Survival in Follicular B-Cell Lymphomas.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3262-3262
Author(s):  
Wei Yun Ai ◽  
Debra K. Czerwinski ◽  
Rob Tibshirani ◽  
Sandra J. Horning ◽  
Ronald Levy
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Population ◽  
Cell Lymphoma ◽  
Cell Populations ◽  
Activated T Cells ◽  
Biopsy Specimens ◽  
Hla Dr

Abstract Introduction: The function of tumor-infiltrating T cells in lymphoma is unknown. Previous studies have shown that an increased percentage of tumor-infiltrating CD4+ T cells was associated with a better overall survival in diffuse large B-cell lymphoma (Ansell S. et al. JCO 2001; Xu et al., British Journal of Haematology 2001). Furthermore, the CD4+ T cells observed in one study was associated with a CD3+/HLA-DR + phenotype, suggesting that they were activated T helper cells. Recently, a molecular predictor model for follicular lymphoma was reported based on microarray analysis of gene expression within the cell populations of biopsy specimens. Three groups of “predictor genes” were identified: one representing B-cell differentiation and two groups representing genes expressed by T cells and macrophages, respectively (ASH abstract, 2003). This raised the question of whether it was simply the presence of tumor-infiltrating T cells that correlated with clinical outcome as opposed to specific activation pathways within those cells. Purpose: The purpose of this study was to examine whether the percentage of tumor-infiltrating T cells is correlated with prognosis of follicular lymphoma. Patients and Methods: We identified 293 follicular lymphoma patients with clinical outcomes available within the Stanford lymphoma database, who had undergone an excisional biopsy, and whose tumor biopsy specimens had been analyzed by flow cytometry. These patients were diagnosed between 1977 and 2003. Among these patients, 167 (57%) had follicular small cleaved lymphoma, 112 (38%) had follicular mixed lymphoma, and 14 (5%) had follicular large cell lymphoma. A total of 66 deaths were documented. The overall survival was estimated from the time of diagnosis to the time of death or last follow-up. Biopsies had been analyzed for cell surface marker expression by single parameter flow cytometry. The percentage of CD3+, CD4+, CD8+, CD20+, and HLA−DR+ cells was determined directly. We also estimated activated T cells, defined by HLA−DR+ T cells, by subtracting the value for total B cells from the value for HLA + cells. Cell population percentages were treated as continuous variables and related to overall survival, each in a univariate analysis. Results: We found no statistically significant correlation between the percentage of any cell population and overall survival. For each group (CD3+, CD4+, CD8+, and estimated HLA−DR+ T cells), we used the percentage of the cell population to divide patients into 3 subgroups of equal number of patients: low-, medium-, and high-percentage. We then compared Kaplan-Meier curves of the 3 subgroups for each cell population. We found no significant differences in survival among the 3 subgroups for each of the cell populations, CD3+, CD4+, CD8+, and the estimated activated T cells, after correcting for multiple hypotheses testing. Conclusion: The percentage of tumor-infiltrating T cells or T cell subsets was not correlated with survival outcome in patients with follicular lymphoma. This finding provides the basis for building molecular predictive models based on gene expression analysis, which represents not only the presence of certain cells but their physiologic state as well.

Gene Expression Profiling Identifies a Prognostically Favorable Subgroup in AML Independent of Cytogenetic Stratification.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 569-569 ◽  
Author(s):  
Claudia Schoch ◽  
Wolfgang Kern ◽  
Alexander Kohlmann ◽  
Wolfgang Hiddemann ◽  
Sylvia Merk ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Survival Rate ◽  
Clinical Outcome ◽  
Expression Profiling ◽  
Normal Karyotype ◽  
Overall Survival Rate ◽  
Training Set ◽  
Test Set ◽  
Genetic Abnormalities

Abstract Acute myeloid leukemia (AML) is a heterogeneous group of diseases with varying clinical outcome. So far the karyotype of the leukemic blasts as well as molecular genetic abnormalities - both abnormalities on the genomic level - have been proven to be strong prognostic markers. However, even in genetically well defined subgroups clinical outcome is not uniform and a large proportion of AML shows genetic abnormalities of yet unknown prognostic significance. Here we addressed the question whether gene expression profiles are associated with clinical outcome independent of the known genomic abnormalities. Therefore, gene expression analyses were performed using Affymetrix U133A+B oligonucleotide microarrays in a total of 403 AML treated uniformly in the AMLCG studies. This cohort was divided randomly into a training set (n=269) and a test set (n=134). The training set included 18 cases with t(15;17), 22 cases with t(8;21), 29 cases with inv(16), 14 cases with 11q23/MLL-rearrangement, 19 with complex aberrant karyotype and 167 cases with normal karyotype or “other” chromosome aberrations. The respective data for the test set were: 10 t(15;17), 8 t(8;21), 11 inv(16), 8 11q23/MLL, 19 cases with complex aberrant karyotype and 78 with normal karyotype or “other” chromosome aberrations. Based on the clinical outcome the training cohort was divided into 4 equally large subgroups. We trained support vector machines (SVM) with the training set and classified the cases of the test set with the respective most discriminating genes. Next a Kaplan-Meier analysis was performed with the test set cases assigned to prognostic groups 1 to 4 according to SVM classification. Based on the expression level of 100 genes group 1 showed an overall survival rate of 57% at 3 years. 31 of 134 (23%) patients were assigned to this favorable subgroup. They belonged to the following cytogenetic subgroups: t(15;17) n=6, t(8;21) n=4, inv(16) n=3, 11q23/MLL n=4, complex aberrant karyotype n=1 and normal karyotype or “other” chromosome aberration n=13. The overall survival rate of groups 2, 3, and 4 did not differ significantly (17%, 21%, and 19% at 3 years). Among the genes highly expressed in the favorable group were MPO and the transcription factor ATBF1, which regulates CCND1. The unfavorable groups were characterized by a higher expression of the transcription factors ETS2, RUNX1, TCF4, and FOXC1. Interestingly, 10 of the top 40 differentially expressed genes are involved in the TP53-CMYC-pathway with a higher expression of 9 of these in the unfavorable groups (SFRS1, TPD52, NRIP1, TFPI, UBL1, REC8L1, HSF2, ETS2 and RUNX1). In conclusion, gene expression profiling leads to the identification of prognostically important alterations of molecular pathways which have not yet been accounted for by use of cytogenetics. This approach is anticipated to help optimizing therapy for patients with AML.

Signaling Diversity in Human Lymphoma B Cells and in Tumor Infiltrating T Cells Correlates with Follicular Lymphoma Patient Clinical Outcomes

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 377-377
Author(s):  
Jonathan M. Irish ◽  
Roch Houot ◽  
June H. Myklebust ◽  
Debra K. Czerwinski ◽  
Garry P. Nolan ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Overall Survival ◽  
T Cells ◽  
Immune System ◽  
B Cells ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Bcr Signaling ◽  
Human Lymphoma ◽  
Group 1

Abstract Introduction: Flow cytometry analysis of live cells from cryopreserved tumor samples provides the opportunity to study simultaneously the biology of both cancer cells and the patient’s immune system cells. Furthermore, single cell based approaches can identify and quantify subsets within mixed populations, such as heterogeneous primary tumors, without the need to physically separate cells. We have previously used flow cytometry to identify differences in signaling mechanism between healthy human B cells from two differentiation stages and to compare signaling kinetics of tumor and non-malignant B cells within primary human lymphoma specimens1. Methods: Here we used barcoded phospho-specific flow cytometry to measure signaling events in live lymphoma B cells and tumor-infiltrating T cells from follicular lymphoma (FL) tumor samples obtained before patients received therapy. Patients were then stratified according to signaling and clinical outcome was examined within the resulting groups. We examined response to initial chemotherapy, which was a combination of cyclophosphamide, vincristine, and prednisone (cvp), and overall survival, measured as the time from diagnosis to last follow up or mortality. Results: Differences in B cell receptor (BCR) signaling strength and kinetics characterized previously unappreciated diversity within the lymphoma B cell population. In some cases, BCR crosslinking triggered robust phosphorylation of AKT and ERK in one subset of lymphoma cells, while in another lymphoma subset within the same tumor sample, BCR crosslinking did not lead to phosphorylation of either protein. In these cases, both lymphoma B cell subsets expressed BCL2 and surface immunoglobulin heavy and light chain restricted to the tumor isotype. Patients whose lymphoma tumor contained a BCR insensitive cell subset (Group 2) had significantly worse responses to cvp therapy (p = 0.001) and lower overall survival (p = 0.003) than patients whose lymphoma cells displayed more homogeneous BCR signaling (Group 1). We next examined tumor infiltrating T cell signaling in the FL cases from Group 1, where no significant BCR insensitive subset was observed. Within Group 1, differences in the magnitude of IL-2, IL-7, and IL-15 mediated STAT5 phosphorylation in tumor infiltrating T cells further distinguished a set of patients with significantly higher overall survival (p = 0.04). Conclusions: These results identify BCR signaling in lymphoma B cells and cytokine signaling in tumor infiltrating T cells as clinically relevant biomarkers for tracking and isolating lymphoma cell subsets and for monitoring immune system activity during therapy. By following patients over time, we can now determine whether cell intrinsic signaling diversity enables the emergence of therapy insensitive cancer cell subsets.

scholarly journals Follicular Lymphoma Cells Induce Changes in T-Cell Gene Expression and Function: Potential Impact on Survival and Risk of Transformation

2013 ◽  
Vol 31 (21) ◽  
pp. 2654-2661 ◽  
Author(s):  
Shahryar Kiaii ◽  
Andrew J. Clear ◽  
Alan G. Ramsay ◽  
Derek Davies ◽  
Ajanthah Sangaralingam ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
Follicular Lymphoma ◽  
Peripheral Blood ◽  
Molecular Mechanisms ◽  
Prognostic Significance ◽  
Time Lapse ◽  
Immune Microenvironment

Purpose Previous studies have demonstrated the prognostic importance of the immune microenvironment in follicular lymphoma (FL). To investigate the molecular mechanisms during which tumor-infiltrating T cells (TILs) are altered in the FL microenvironment, we studied highly purified CD4 and CD8 TILs from lymph node biopsies at diagnosis in treatment-naive patients with FL compared with reactive tonsils and the peripheral blood of healthy donors. Patients and Methods Gene expression profiling of highly purified CD4 and CD8 TILs was performed on the Affymetrix platform. Diagnostic tissue microarrays from an independent patient set (n = 172) were used to verify protein expression and analyze any impact of TIL-expressed genes on outcome. Time-lapse imaging was used to assess T-cell motility. Results The most upregulated genes in both CD4 and CD8 TILs were PMCH, ETV1, and TNFRSF9. PMCH is not expressed in peripheral blood T cells, but expression is highly induced on culture with FL. Both CD4 and CD8 TILs from patients with FL have significantly impaired motility compared with those of healthy TILs from reactive tonsils and this can be induced on healthy T cells by FL cells. During multivariate analysis, a model incorporating the number and location of T cells expressing PMCH, NAMPT, and ETV1 showed prognostic significance for overall survival and for time to transformation. Conclusion We showed altered gene expression in TILs in FL and demonstrated that altering the immune microenvironment in FL affects overall survival and time to transformation in this disease.

scholarly journals A Proinflammatory Invariant Natural Killer T Cells Phenotypic State Associates with Human Graft-Versus-Host Disease Onset and Response

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2111-2111
Author(s):  
Tom Erkers ◽  
Bryan Xei ◽  
Laura Kenyon ◽  
Mary Rieck ◽  
Marina Basina ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Gene Signature ◽  
Inkt Cells ◽  
Transplant Patients ◽  
Hla Dr ◽  
Cell Gene ◽  
Killer T Cells

Abstract Human invariant natural killer T cells (iNKT) are a rare population of lymphocytes that bridges innate and adaptive immune functions. iNKT cells have different potent effector functions and subsets, but this heterogeneity is mostly understood by a superimposed framework of classic T cell markers. This may help explain contradictory studies of iNKT cells in diseases for which they are thought to play a pathogenic role. In this study, we present data suggesting new markers to understand human iNKT cell heterogeneity and function, as well as monitoring this in the clinical context of allogeneic stem cell transplantation (ASCT) and graft-versus-host disease (GVHD). In both preclinical murine models and in correlative clinical studies, iNKT cells are associated with less GVHD and better immune reconstitution following ASCT. We performed bulk whole transcriptome sequencing on iNKT cells from patients at day +30 after ASCT, some who developed and some who did not develop GVHD. Gene expression signatures of the iNKT cells from each individual are grouped based on a transcriptome library of reference cell types (CIBERSORT). Using this approach, we distinguished patients who will develop GVHD as predominately having an activated cytotoxic cell gene signature, whereas patients without GVHD had a CD4+ T cell gene signature within purified peripheral blood iNKT cells. Using two different high throughput single-cell RNA sequencing (sc-seq) platforms to determine differential gene expression on the single cell level, we first examined the gene expression signatures of primary human iNKT cells from healthy donors. Activation with CD3/28 microbeads of primary iNKT cells promoted two main differential transcriptional profiles in iNKT cells. One profile resembles conventional CD4+ T cells and associated Th2 cytokine profile (IL2, IL4), whereas the other profile has genes associated with cytotoxicity and inflammation (TNF, IFNG, GZMB). Confirmation by flow cytometry showed that while CD8 surface expression did not well differentiate the pro-inflammatory and cytotoxic subsets, but both CD94 and KLRG1 better associate with Th1 and cytotoxic responses. CD94+ iNKT are restricted to CD4- cells and KLRG1 expressed in both CD4+ and CD4- populations. By comparison, the analysis of sc-seq of normal healthy subjects and post-transplant patients with and without GVHD resulted in the identification of three major iNKT populations. The population most associated with GVHD showed expression of a pro-inflammatory profile enriched for CXCR4,CD94, HLA-DRB1/A1 and decreased KLRB1. Whereas, post-transplant patients with healthy GVHD-free and relapse free immune reconstitution showed a more T cell like profile but with increased expression of CXCR4, CD94, KLRB1 and decreased HLA-DRB1/A1. Using flow cytometry of ex vivo expanded iNKT cells, we found the expansion of CXCR4+HLA-DR+ that can be CD4+ or CD4- and that these cells produce high levels of the cytokine TNF-a, IFN-g and IL-4. Importantly, iNKT cells that are CXC4+HLA-DR+KLRB1low make significantly less IL-4 and these are enriched in the GVHD setting. Using flow cytometry, we measured iNKT cell phenotypes in a pilot cohort of 48 individuals; 10 healthy controls, 10 patients with no complications or relapse after ASCT and 18 patients with GVHD of which 9 were steroid refractory. In addition, we evaluated 11 patients with new onset T1D. The frequency of the cytotoxic CD94+ iNKT cells were significantly increased in all patients following and in T1D compared to healthy controls. Whereas, patients with GVHD showed an increase in HLA-DR+CXCR4+KLRB1low iNKT cells. Increases in the late activation marker HLA-DR distinguished corticosteroid refractory (HLA-DR++) from steroid responsive patients at the time of initial GVHD diagnosis. For patients who responded to steroids or further therapy, we found that a reduction in HLA-DR associated with treatment response. In a second 24 patient cohort, we found that the presence HLA-DR+CXCR4+CD161low cells at day +30 was statistically greater in patients who would go on to develop GVHD as compared as those who did not (student T test, p<0.01) To conclude, we have used different methods to discover and validate groups of iNKT cells with distinct functions, and the associated phenotype correlate with clinical inflammation both following ASCT and in T1D. Disclosures No relevant conflicts of interest to declare.

scholarly journals An Immune Cell-Based Signature Associating With EMT Phenotype Predicts Postoperative Overall Survival of ESCC

2021 ◽  
Vol 11 ◽  
Author(s):  
Hongliang Yu ◽  
Dayong Gu ◽  
Chao Yue ◽  
Jianhua Xu ◽  
Feng Yan ◽  
...  
Keyword(s):  
Gene Expression ◽  
Overall Survival ◽  
Immune Cell ◽  
Gene Set Enrichment Analysis ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Survival Times ◽  
Training Set ◽  
Mesenchymal Transition ◽  
Validation Set

Esophageal squamous cell carcinoma (ESCC) is one of the deadliest solid malignancies and has a poor survival rate worldwide. In this study, we aimed to establish a tumor-infiltrating immune cell-based prognosis signature (IPS) to predict patients’ survival times and aid in the development of targeted therapies or immunotherapies. The abundances of 22 types of immune cells were determined by the CIBERSORT algorithm from ESCC patient gene expression data in the Gene Expression Omnibus (GEO) training set (n = 179) and The Cancer Genome Atlas (TCGA) validation set (n = 95). Then, the IPS was established by using the least absolute shrinkage and selection operator (LASSO) regression method. Kaplan-Meier analysis showed that patients with high IPS scores had significantly worse overall survival times than patients with low IPS scores in both the training set and the validation set (log-rank p = 0.001, and p = 0.050, respectively). Univariate and multivariate Cox regression analyses proved that the IPS was a robust prognostic factor for ESCC, independent of age, sex, tumor node metastasis (TNM) stage, pathology grade, and tumor location. In the mechanistic study, the epithelial-mesenchymal transition (EMT) process was identified by both gene set enrichment analysis (GSEA) and weighted correlation network analysis (WGCNA) as the underlying mechanism by which the IPS affects the prognosis of ESCC. After systematic correlation analyses, we found that M2 macrophages were the only cell type in the IPS significantly correlated with the EMT process. This relationship between M2 macrophage infiltration and the EMT phenotype was also confirmed by our preliminary immunochemistry (IHC) and multiplexed immunofluorescence study. In conclusion, we constructed an IPS that predicts the postoperative prognosis of ESCC patients and uncovered the critical role of M2 macrophages in the interplay between immune status and the EMT phenotype in ESCC.

scholarly journals Evaluation of the Expression of CCR5 and CX3CR1 Receptors and Correlation with the Functionality of T Cells in Women infected with ZIKV during Pregnancy

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 191
Author(s):  
Débora Familiar-Macedo ◽  
Iury Amancio Paiva ◽  
Jessica Badolato-Corrêa da Silva ◽  
Fabiana Rabe de Carvalho ◽  
Helver Gonçalves Dias ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
Clinical Outcome ◽  
Cell Responses ◽  
Functional Assays ◽  
Asymptomatic Children ◽  
Cd107a Expression ◽  
Congenital Zika Syndrome ◽  
Ifn Γ

There have been reports of neurological abnormalities associated with the Zika virus (ZIKV), such as congenital Zika syndrome (CZS) in children born to mothers infected during pregnancy. We investigated how the immune response to ZIKV during pregnancy is primed and conduct a thorough evaluation of the inflammatory and cytotoxic profiles as well as the expression of CCR5 and CX3CR1. We compared the reactivity of T cells to ZIKV peptides in convalescent mothers infected during pregnancy. The child’s clinical outcome (i.e., born with or without CZS) was taken to be the variable. The cells were stimulated in vitro with ZIKV peptides and evaluated using the ELISPOT and flow cytometry assays. After in vitro stimulation with ZIKV peptides, we observed a tendency toward a higher Interferon gamma (IFN-γ)-producing T cell responses in mothers who had asymptomatic children and a higher CD107a expression in T cells in mothers who had children with CZS. We found a higher frequency of T cells expressing CD107a+ and co-expressing CX3CR1+CCR5+, which is much clearer in the T cells of mothers who had CZS children. We suggest that this differential profile influenced the clinical outcome of babies. These data need to be further investigated, including the evaluation of other ZIKV peptides and markers and functional assays.

High numbers of tumor-infiltrating FOXP3-positive regulatory T cells are associated with improved overall survival in follicular lymphoma

Blood ◽  
2006 ◽  
Vol 108 (9) ◽  
pp. 2957-2964 ◽  
Author(s):  
Joaquim Carreras ◽  
Armando Lopez-Guillermo ◽  
Bridget C. Fox ◽  
Lluis Colomo ◽  
Antonio Martinez ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
Regulatory T Cells ◽  
Follicular Lymphoma ◽  
International Prognostic Index ◽  
Prognostic Significance ◽  
Prognostic Index ◽  
Specific Cell ◽  
First Relapse ◽  
The Impact

Abstract The tumor microenvironment plays an important role in the biologic behavior of follicular lymphoma (FL), but the specific cell subsets involved in this regulation are unknown. To determine the impact of FOXP3-positive regulatory T cells (Tregs) in the progression and outcome of FL patients, we examined samples from 97 patients at diagnosis and 37 at first relapse with an anti-FOXP3 monoclonal antibody. Tregs were quantified using computerized image analysis. The median overall survival (OS) of the series was 9.9 years, and the FL International Prognostic Index (FLIPI) was prognostically significant. The median Treg percentage at diagnosis was 10.5%. Overall, 49 patients had more than 10% Tregs, 30 between 5% to 10%, and 19 less than 5%, with a 5-year OS of 80%, 74%, and 50%, respectively (P = .001). Patients with very low numbers of Tregs (< 5%) presented more frequently with refractory disease (P = .007). The prognostic significance of Treg numbers was independent of the FLIPI. Seven transformed diffuse large B-cell lymphomas (DLBCLs) had lower Treg percentages (mean: 3.3%) than FL grades 1,2 (mean: 12.1%) or 3 (mean: 9%) (P < .02). In conclusion, high Treg numbers predict improved survival of FL patients, while a marked reduction in Tregs is observed on transformation to DLBCL.

scholarly journals Graft-Versus-Host Disease–Free Antitumoral Signature After Allogeneic Donor Lymphocyte Injection Identified by Proteomics and Systems Biology

2019 ◽  
pp. 1-11 ◽  
Author(s):  
Xiaowen Liu ◽  
Zongliang Yue ◽  
Yimou Cao ◽  
Lauren Taylor ◽  
Qing Zhang ◽  
...  
Keyword(s):  
T Cells ◽  
Systems Biology ◽  
Graft Versus Host Disease ◽  
Acute Gvhd ◽  
Hematopoietic Cell Transplantation ◽  
Training Set ◽  
Activated T Cells ◽  
Graft Versus Host ◽  
Single Cell Profiling ◽  
Validation Set

PURPOSE As a tumor immunotherapy, allogeneic hematopoietic cell transplantation with subsequent donor lymphocyte injection (DLI) aims to induce the graft-versus-tumor (GVT) effect but often also leads to acute graft-versus-host disease (GVHD). Plasma tests that can predict the likelihood of GVT without GVHD are still needed. PATIENTS AND METHODS We first used an intact-protein analysis system to profile the plasma proteome post-DLI of patients who experienced GVT and acute GVHD for comparison with the proteome of patients who experienced GVT without GVHD in a training set. Our novel six-step systems biology analysis involved removing common proteins and GVHD-specific proteins, creating a protein-protein interaction network, calculating relevance and penalty scores, and visualizing candidate biomarkers in gene networks. We then performed a second proteomics experiment in a validation set of patients who experienced GVT without acute GVHD after DLI for comparison with the proteome of patients before DLI. We next combined the two experiments to define a biologically relevant signature of GVT without GVHD. An independent experiment with single-cell profiling in tumor antigen–activated T cells from a patient with post–hematopoietic cell transplantation relapse was performed. RESULTS The approach provided a list of 46 proteins in the training set, and 30 proteins in the validation set were associated with GVT without GVHD. The combination of the two experiments defined a unique 61-protein signature of GVT without GVHD. Finally, the single-cell profiling in activated T cells found 43 of the 61 genes. Novel markers, such as RPL23, ILF2, CD58, and CRTAM, were identified and could be extended to other antitumoral responses. CONCLUSION Our multiomic analysis provides, to our knowledge, the first human plasma signature for GVT without GVHD. Risk stratification on the basis of this signature would allow for customized treatment plans.

Sign in / Sign up

Export Citation Format

Share Document