scholarly journals Circulating myeloid-derived suppressor cells and regulatory T cells as immunological biomarkers in refractory/relapsed diffuse large B-cell lymphoma: translational results from the R2-GDP-GOTEL trial

2021 ◽  
Vol 9 (6) ◽  
pp. e002323
Author(s):  
Carlos Jiménez-Cortegana ◽  
Natalia Palazón-Carrión ◽  
Alejandro Martin Garcia-Sancho ◽  
Esteban Nogales-Fernandez ◽  
Fernando Carnicero-González ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
T Lymphocytes ◽  
B Cell ◽  
Cell Lymphoma ◽  
Suppressor Cells ◽  
B Cell Lymphoma ◽  
Myeloid Derived Suppressor Cells ◽  
Large B Cell Lymphoma ◽  
Large B Cell

BackgroundThe search for immunological markers with ability of predicting clinical outcome is a priority in lymphomas, and in cancer in general. It is well known that some immunomodulatory cells, such as myeloid derived suppressor cells (MDSCs) or regulatory T cells (Tregs), are recruited by tumors, jeopardizing antitumor immunosurveillance. In this work, we have studied blood levels of these immunosuppressive cells in patients with relapsed/refractory diffuse large B-cell lymphoma (R/R DLBCL), prior to and along the course of the experimental rituximab, gemcitabine, dexamethasone, and cisplatin (R2-GDP) schedule, as a translational substudy of the R2-GDP-GOTEL trial (EudraCT Number: 2014-001620-29), which included lenalidomide as an immunomodulator.MethodsBlood samples were taken before treatment, at cycle 3 and end of induction. Samples were analyzed by flow cytometry. Non-parametric tests were used. Mann-Whitney U test was used to compare basal cells distributions, and Wilcoxon test was considered to compare cells distribution at different times. Spearman test was performed to measure the degree of association between cell populations.ResultsIn this study, MDSC and Treg circulating concentration was found increased in all patients compared with a healthy control group and decreased after treatment only in patients with longest overall survival (>24 months), reaching the levels of the healthy group. Likewise, the number of inhibited T lymphocytes expressing Programmed Death-1 (PD-1) were increased in peripheral blood from patients and decreased on the treatment, whereas activated T lymphocytes increased after therapy in those with better overall survival.ConclusionsIn conclusion, blood concentration of MDSCs and Treg cells may be good prognostic markers for overall survival after 2 years in R/R DLBCL. These results point to a possible role of these elements in the immunosuppression of these patients, as assessed by the circulating activated and inhibited T lymphocytes, and therefore, they may be considered as therapeutic targets in DLBCL.

Gender and Tumor Infiltrating Regulatory T-Cells Have Paradoxical Effects on Survival in Patients with Diffuse Large B-Cell Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 5288-5288
Author(s):  
Anthony P Lam ◽  
Bruce E Petersen ◽  
Ira Braunschweig ◽  
Howard Ratech
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Large B Cell Lymphoma ◽  
And Gender ◽  
The Relationship ◽  
Gender Specific ◽  
Large B Cell

Abstract Introduction: Among patients with diffuse large B-cell lymphoma (DLBCL), it is well documented that for unknown reasons men have shorter progression-free and overall survival than women. Recently, a specialized subset of CD4+ T-cells, called regulatory T-cells (T-regs), which can suppress the effector functions of cytotoxic CD8+ T-cells, has been proposed to have a role in controlling tumor progression. While elevated T-regs in animal models of cancer can block anti-tumor responses and thereby enhance tumor growth, paradoxically, high T-regs are associated with improved survival in humans with DLBCL. To our knowledge, the relationship between T-regs and gender has not been investigated. Since T-regs constitutively express FoxP3, a transcription factor of the forkhead family, we used this marker to retrospectively study the number and density of FoxP3+ T-regs in tissue sections from both male and female patients with DLBCL, and to compare their effects on survival. Methods: Tumor microarrays of DLBCL containing three 1 mm diameter cores per patient were immunohistochemically stained for FoxP3 and CD4. We enumerated tumor infiltrating FoxP3+ lymphocytes by counting positive nuclei that crossed the lines of a 1 mm2 10×10 grid in a 10× ocular that was combined with a 40× objective in a BX41 Olympus microscope. The mean FoxP3 T-regs per field and the ratio of FoxP3 T-regs to total CD4+ T-cells were compared between 34 men and 48 women with de novo, non-AIDS related DLBCL. The median values were used as cut-offs for total FoxP3 counts and for FoxP3/CD4 ratios. We analyzed survival differences between “high” and “low” groups by using Kaplan-Meier curves and Logrank tests. Cox regression analyses were used to compare mortality after adjusting for age and staging. Results: Men had lower values than women both for mean total FoxP3 counts (7.05 vs 8.15, p=0.636) and for mean FoxP3/CD4 ratios (0.31 vs 0.51, p=0.183). Differences between genders in the proportion above the overall median (“high” group) were statistically significant when comparing total FoxP3 counts (32.4% in men vs. 60.4% in women, p=0.012) and FoxP3/CD4 ratios (35.3% vs. 58.3%, p=0.040). Using gender-specific cut-offs, higher FoxP3/CD4 ratios were associated with worse overall survival in men (Figure 1, p=0.052), but improved overall survival in women (Figure 2, p=0.047). The crude hazard ratio comparing groups with gender-specific “high” vs. “low” FoxP3/CD4 ratios was 3.99 (p=0.077) in men and 0.33 (p=0.061) in women. Adjusting for age did not result in significant changes, but adjusting for stage at diagnosis shifted the hazard ratios toward the null (1.06, p=0.947 in men and 0.45, p=0.218 in women). In men, those in the “high” FOXP3/CD4 ratio group appeared more likely to have stage 3 or 4 disease at diagnosis compared to the “low” group (66.7% vs 36.8%, p=0.139). This was not seen in women (33.3% vs 38.9%, p=0.718). Conclusions: More T-regs infiltrated DLBCL in women than in men. This is difficult to explain, but could be a clue to the relationship between survival and gender in DLBCL. Paradoxically, high T-regs predicted worse overall survival in men, but better overall survival in women. Also, stage 3 or 4 disease at diagnosis was associated with high T-regs in men but not in women. To confirm the significance of these findings, a larger sample size and prospective study design will be needed. Figure 1 Survival in Men with DLBCL by FoxP3/CD4
 p=0.052 Figure 1. Survival in Men with DLBCL by FoxP3/CD4
 p=0.052 Figure 2 Survival in Women with DLBCL by FoxP3/CD4
 p=0.048 Figure 2. Survival in Women with DLBCL by FoxP3/CD4
 p=0.048

MAL Is Expressed in a Subset of Hodgkin Lymphomas and Identifies a Population of Patients with Poor Prognosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 3117-3117
Author(s):  
Eric D. Hsi ◽  
Stephen J. Sup ◽  
Carlos Alemany ◽  
Elisa Tso ◽  
Marek Skacel ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cells ◽  
B Cell ◽  
Lipid Rafts ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Receptor Activation ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Recent evidence suggests that classical Hodgkin lymphoma (cHL) and primary mediastinal diffuse large B-cell lymphoma (PMLBL) have similarities that span clinical, histopathologic, and molecular genetic features. MAL is a gene that encodes a protein associated with lipid rafts in T-cells and epithelial cells. In T-cells, it is involved in the reorganization of lipid rafts during T-cell receptor activation and signaling. MAL is overexpressed in PMLBL and in a minority of cHL cases; however, data on its expression in a large series of cHL with clinical follow-up is lacking. In order to determine whether there might be some clinical significance associated with MAL expression, we evaluated MAL expression in a series of cHL by immunohistochemistry. Clinical information including age, sex, stage, bulky tumors (≥ 1/3 of the thoracic diameter or mass ≥ 10cm), hemoglobin, WBC, lymphocyte count, albumin, and outcome were collected for the cHL patients. Tissue microarrays containing diffuse large B-cell lymphoma (n=33), PMLBL (n=41), and cHL (n=87) were stained for MAL. 54% of PBLBL, 17% of cHL, and 3% of non-mediastinal diffuse large B-cell lymphomas were found to express MAL. Focussing on cHL, MAL expression correlated with the nodular sclerosis histologic subtype (P=0.03, Fisher exact). Overall, 22 HL patients have failed (relapse or death) and 15 patients have died. Median follow-up of patients alive and free of disease is 6.7 years (range 1.0–16.9 years). The 5-year failure-free and overall survival are 75 +/− 5% and 85 +/−4%, respectively. Using P<0.1 as significant, univariable analysis (Wilcoxon rank sum) showed that the following factors were associated with shorter failure free survival and overall survival: age ≥ 45 (P=0.01 and P<0.001, respectively), stage III/IV (P=0.09 and P=0.03, respectively), and MAL expression (P=0.05 and P=0.01, respectively). Cox proportional hazards modeling showed that the following were independent predictors of both time to treatment failure and overall survival: age (P=0.03 and 0.01, respectively), stage (P=0.06 and 0.04, respectively), and MAL expression (P=0.06 and 0.02, respectively). These data suggest that MAL expression in cHL identifies a biologically different subset of cHL compared to those cases that lack MAL and that MAL expression is a predictor of adverse outcome.

scholarly journals Gene expression profiling-based risk prediction and profiles of immune infiltration in diffuse large B-cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Selin Merdan ◽  
Kritika Subramanian ◽  
Turgay Ayer ◽  
Johan Van Weyenbergh ◽  
Andres Chang ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
B Cell ◽  
Risk Prediction ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Gene Signatures ◽  
Large B Cell Lymphoma ◽  
Large B Cell

AbstractThe clinical risk stratification of diffuse large B-cell lymphoma (DLBCL) relies on the International Prognostic Index (IPI) for the identification of high-risk disease. Recent studies suggest that the immune microenvironment plays a role in treatment response prediction and survival in DLBCL. This study developed a risk prediction model and evaluated the model’s biological implications in association with the estimated profiles of immune infiltration. Gene-expression profiling of 718 patients with DLBCL was done, for which RNA sequencing data and clinical covariates were obtained from Reddy et al. (2017). Using unsupervised and supervised machine learning methods to identify survival-associated gene signatures, a multivariable model of survival was constructed. Tumor-infiltrating immune cell compositions were enumerated using CIBERSORT deconvolution analysis. A four gene-signature-based score was developed that separated patients into high- and low-risk groups. The combination of the gene-expression-based score with the IPI improved the discrimination on the validation and complete sets. The gene signatures were successfully validated with the deconvolution output. Correlating the deconvolution findings with the gene signatures and risk score, CD8+ T-cells and naïve CD4+ T-cells were associated with favorable prognosis. By analyzing the gene-expression data with a systematic approach, a risk prediction model that outperforms the existing risk assessment methods was developed and validated.

scholarly journals Elevated M-MDSCs in Circulation Are Indicative of Poor Prognosis in Diffuse Large B-Cell Lymphoma Patients

2021 ◽  
Vol 10 (8) ◽  
pp. 1768
Author(s):  
Zhitao Wang ◽  
Rui Jiang ◽  
Qian Li ◽  
Huiping Wang ◽  
Qianshan Tao ◽  
...  
Keyword(s):  
B Cell ◽  
Poor Prognosis ◽  
Cell Lymphoma ◽  
Suppressor Cells ◽  
B Cell Lymphoma ◽  
Pathological Process ◽  
Newly Diagnosed ◽  
Large B Cell Lymphoma ◽  
Accumulation Mechanism ◽  
Large B Cell

Myeloid-derived suppressor cells (MDSCs) are defined as negative regulators that suppress the immune response through a variety of mechanisms, which usually cluster in cancer, inflammation, and autoimmune diseases. This study aims to investigate the correlation between M-MDSCs and the clinical features of diffuse large B-cell lymphoma (DLBCL) patients, as well as the possible accumulation mechanism of M-MDSCs. The level of M-MDSCs is significantly increased in newly diagnosed and relapsed DLBCL patients. Regarding newly diagnosed DLBCL patients, the frequency of M-MDSCs is positively correlated with tumor progression and negatively correlated with overall survival (OS). More importantly, the level of M-MDSCs can be defined as a biomarker for a poor prognosis in DLBCL patients. Additionally, interleukin-35 (IL-35) mediates the accumulation of M-MDSCs in DLBCL patients. Anti-IL-35 treatment significantly reduces levels of M-MDSCs in Ly8 tumor-bearing mice. Thus, M-MDSCs are involved in the pathological process of DLBCL. Targeting M-MDSCs may be a promising therapeutic strategy for the treatment of DLBCL patients.

scholarly journals Use of immune repertoire sequencing to resolve discordant microscopic and immunochemical findings in a case of T cell-rich large B cell lymphoma in a young dog

2021 ◽  
Vol 17 (1) ◽  
Author(s):  
Gary Kwok Cheong Lee ◽  
Dorothee Bienzle ◽  
Stefan Matthias Keller ◽  
Mei-Hua Hwang ◽  
Nikos Darzentas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Immune Repertoire ◽  
Large B Cell Lymphoma ◽  
Repertoire Sequencing ◽  
Reactive Lymphocytes ◽  
Large B Cell

Abstract Background Lymphocytic neoplasms with frequent reactive lymphocytes are uncommonly reported in dogs, and can pose a diagnostic challenge. Different diagnostic modalities such as cytology, flow cytometry, histopathology, immunohistochemistry, and clonality testing, are sometimes required for a diagnosis. This report illustrates the value of using a multi-modal diagnostic approach to decipher a complex lymphocytic tumor, and introduces immune repertoire sequencing as a diagnostic adjunct. Case presentation A 10-month-old Great Dane was referred for marked ascites. Cytologic analysis of abdominal fluid and hepatic aspirates revealed a mixed lymphocyte population including numerous large lymphocytes, yielding a diagnosis of lymphoma. Flow cytometrically, abdominal fluid lymphocytes were highly positive for CD4, CD5, CD18, CD45, and MHC II, consistent with T cell lymphoma. Due to a rapidly deteriorating clinical condition, the dog was euthanized. Post mortem histologic evaluation showed effacement of the liver by aggregates of B cells surrounded by T cells, suggestive of hepatic T cell-rich large B cell lymphoma. Immune repertoire sequencing confirmed the presence of clonal B cells in the liver but not the abdominal fluid, whereas reactive T cells with shared, polyclonal immune repertoires were found in both locations. Conclusions T cell-rich large B cell lymphoma is a rare neoplasm in dogs that may be challenging to diagnose and classify due to mixed lymphocyte populations. In this case, the results of histopathology, immunohistochemistry and immune repertoire sequencing were most consistent with a hepatic B cell neoplasm and reactive T cells exfoliating into the abdominal fluid. Immune repertoire sequencing was helpful in delineating neoplastic from reactive lymphocytes and characterizing repertoire overlap in both compartments. The potential pitfalls of equating atypical cytomorphology and monotypic marker expression in neoplasia are highlighted.

scholarly journals Treatment factors affecting outcomes in HIV-associated non-Hodgkin lymphomas: a pooled analysis of 1546 patients

Blood ◽  
2013 ◽  
Vol 122 (19) ◽  
pp. 3251-3262 ◽  
Author(s):  
Stefan K. Barta ◽  
Xiaonan Xue ◽  
Dan Wang ◽  
Roni Tamari ◽  
Jeannette Y. Lee ◽  
...  
Keyword(s):  
Overall Survival ◽  
B Cell ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Pooled Analysis ◽  
Factors Affecting ◽  
Large B Cell Lymphoma ◽  
Key Points ◽  
Large B Cell

Key Points Rituximab use is associated with significant improvement in all outcomes for patients with HIV-associated CD20-positive lymphomas. Infusional EPOCH chemotherapy is associated with better overall survival in patients with AIDS-related diffuse large B-cell lymphoma (DLBCL).

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