scholarly journals EOMES and IL-10 regulate anti-tumor activity of PD-1+ CD4+ T-cells in B-cell Non-Hodgkin lymphoma

2020 ◽  
Author(s):  
Philipp M. Roessner ◽  
Laura Llaó Cid ◽  
Ekaterina Lupar ◽  
Tobias Roider ◽  
Marie Bordas ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Activities ◽  
Dependent Manner ◽  
Non Hodgkin Lymphoma ◽  
T Cell Transfer

AbstractThe transcription factor Eomesodermin (EOMES) promotes IL-10 production of CD4+ T-cells, which has been linked to immunosuppressive and cytotoxic activities. We detected EOMES-expressing CD4+ T-cells in lymph node samples of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. This was in line with an observed expansion of EOMES-positive CD4+ T-cells in leukemic Eµ-TCL1 mice, a well-established model of CLL, and upon adoptive transfer of TCL1 leukemia in mice. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive the transcription of IL-10, but rather controls a unique differentiation program in CD4+ T-cells. Moreover, EOMES was necessary for the accumulation of a specific CD4+ T-cell subset that expresses IFNγ and IL-10, as well as inhibitory receptors, like PD-1 and LAG3. T-cell transfer studies in leukopenic Rag2-/- mice showed that EOMES-deficient CD4+ T-cells were inferior in controlling TCL1 leukemia development compared to wildtype T-cells, even though expansion of Eomes-/- CD4+ T-cells was observed. We further showed that control of TCL1 leukemia was driven by IL-10 receptor-mediated signals, as Il10rb-deficient CD4+ T-cells showed impaired anti-leukemia activity. Altogether, our data suggest that IL-10 producing PD-1+ CD4+ T-cells contribute to CLL control in an EOMES- and IL-10R-dependent manner.

scholarly journals Emergence of CD52-, phosphatidylinositolglycan-anchor-deficient T lymphocytes after in vivo application of Campath-1H for refractory B- cell non-Hodgkin lymphoma

Blood ◽  
1995 ◽  
Vol 86 (4) ◽  
pp. 1487-1492 ◽  
Author(s):  
B Hertenstein ◽  
B Wagner ◽  
D Bunjes ◽  
C Duncker ◽  
A Raghavachar ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Molecular Characteristics ◽  
T Cell Clones ◽  
Non Hodgkin Lymphoma ◽  
Cell Clones ◽  
Immune Attack

CD52 is a phosphatidylinositolglycan (PIG)-anchored glycoprotein (PIG- AP) expressed on normal T and B lymphocytes, monocytes, and the majority of B-cell non-Hodgkin lymphomas. We observed the emergence of CD52- T cells in 3 patients after intravenous treatment with the humanized anti-CD52 monoclonal antibody Campath-1H for refractory B- cell lymphoma and could identify the underlaying mechanism. In addition to the absence of CD52, the PIG-AP CD48 and CD59 were not detectable on the CD52- T cells in 2 patients. PIG-AP-deficient T-cell clones from both patients were established. Analysis of the mRNA of the PIG-A gene showed an abnormal size in the T-cell clones from 1 of these patients, suggesting that a mutation in the PIG-A gene was the cause of the expression defect of PIG-AP. An escape from an immune attack directed against PIG-AP+ hematopoiesis has been hypothesized as the cause of the occurrence of PIG-AP-deficient cells in paroxysmal nocturnal hemoglobinuria (PNH) and aplastic anemia. Our results support the hypothesis that an attack against the PIG-AP CD52 might lead to the expansion of a PIG-anchor-deficient cell population with the phenotypic and molecular characteristics of PNH cells.

scholarly journals Flow Cytometric Detection of the Double-Positive (CD4+CD8+)/PD-1bright T-Cell Subset Is Useful in Diagnosing Nodular Lymphocyte-Predominant Hodgkin Lymphoma

2021 ◽  
Author(s):  
Zhongchuan Will Chen ◽  
Juanita Wizniak ◽  
Chuquan Shang ◽  
Raymond Lai
Keyword(s):  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
The Other ◽  
Non Hodgkin Lymphoma ◽  
Flow Cytometric ◽  
Large B Cell

Context.— Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is characterized by neoplastic lymphocyte-predominant cells frequently rimmed by CD3+/CD57+/programmed death receptor-1 (PD-1)+ T cells. Because of the rarity of lymphocyte-predominant cells in most cases, flow cytometric studies on NLPHL often fail to show evidence of malignancy. Objective.— To evaluate the diagnostic utility of PD-1 in detecting NLPHL by flow cytometry, in conjunction with the CD4:CD8 ratio and the percentage of T cells doubly positive for CD4 and CD8. Design.— Flow cytometric data obtained from cases of NLPHL (n = 10), classical Hodgkin lymphoma (n = 20), B-cell non-Hodgkin lymphoma (n = 22), T-cell non-Hodgkin lymphoma (n = 5), benign lymphoid lesions (n = 20), angioimmunoblastic T-cell lymphomas (n = 6) and T-cell/histiocyte–rich large B-cell lymphomas (n = 2) were analyzed and compared. Results.— Compared with the other groups, NLPHL showed significantly higher values in the following parameters: CD4:CD8 ratio, percentage of T cells doubly positive for CD4 and CD8, percentage of PD-1–positive T cells, and median fluorescence intensity of PD-1 expression in the doubly positive for CD4 and CD8 subset. Using a scoring system (0–4) based on arbitrary cutoffs for these 4 parameters, all 10 NLPHL cases scored 3 or higher, as compared with only 3 cases from the other groups, producing an overall sensitivity of 100% and a specificity of 96% (72 of 75). Two of the 3 outliers were non-Hodgkin lymphoma, and both showed definitive immunophenotypic abnormalities leading to the correct diagnosis. The remaining outlier was a case of T-cell/histiocyte–rich large B-cell lymphoma. Conclusions.— The inclusion of anti–PD-1 in flow cytometry is useful for detecting NLPHL in fresh tissue samples, most of which would have otherwise been labeled as nondiagnostic or reactive lymphoid processes.

scholarly journals Overcoming the Hurdles of Autologous T-Cell-Based Therapies in B-Cell Non-Hodgkin Lymphoma

Cancers ◽  
2020 ◽  
Vol 12 (12) ◽  
pp. 3837
Author(s):  
Jaco A. C. van Bruggen ◽  
Anne W. J. Martens ◽  
Sanne H. Tonino ◽  
Arnon P. Kater
Keyword(s):  
T Cell ◽  
B Cell ◽  
Cell Lymphoma ◽  
Clinical Success ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
T Cell Subsets ◽  
Treatment Modalities ◽  
Cellular Immunotherapy

The next frontier towards a cure for B-cell non-Hodgkin lymphomas (B-NHL) is autologous cellular immunotherapy such as immune checkpoint blockade (ICB), bispecific antibodies (BsAbs) and chimeric antigen receptor (CAR) T-cells. While highly successful in various solid malignancies and in aggressive B-cell leukemia, this clinical success is often not matched in B-NHL. T-cell subset skewing, exhaustion, expansion of regulatory T-cell subsets, or other yet to be defined mechanisms may underlie the lack of efficacy of these treatment modalities. In this review, a systematic overview of results from clinical trials is given and is accompanied by reported data on T-cell dysfunction. From these results, we distill the underlying pathways that might be responsible for the observed differences in clinical responses towards autologous T-cell-based cellular immunotherapy modalities between diffuse large B-cell lymphoma (DLBCL), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), mantle cell lymphoma (MCL), and marginal zone lymphoma (MZL). By integration of the clinical and biological findings, we postulate strategies that might enhance the efficacy of autologous-based cellular immunotherapy for the treatment of B-NHL.

scholarly journals EOMES and IL-10 regulate antitumor activity of T regulatory type 1 CD4+ T cells in chronic lymphocytic leukemia

Leukemia ◽  
2021 ◽  
Author(s):  
Philipp M. Roessner ◽  
Laura Llaó Cid ◽  
Ekaterina Lupar ◽  
Tobias Roider ◽  
Marie Bordas ◽  
...  
Keyword(s):  
T Cells ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell Lymphoma ◽  
Lymphocytic Leukemia ◽  
Cytotoxic Activities ◽  
Dependent Manner ◽  
Transcriptional Signature ◽  
And Control ◽  
Regulatory Type

AbstractThe transcription factor eomesodermin (EOMES) promotes interleukin (IL)-10 expression in CD4+ T cells, which has been linked to immunosuppressive and cytotoxic activities. We detected cytotoxic, programmed cell death protein-1 (PD-1) and EOMES co-expressing CD4+ T cells in lymph nodes (LNs) of patients with chronic lymphocytic leukemia (CLL) or diffuse large B-cell lymphoma. Transcriptome and flow cytometry analyses revealed that EOMES does not only drive IL-10 expression, but rather controls a unique transcriptional signature in CD4+ T cells, that is enriched in genes typical for T regulatory type 1 (TR1) cells. The TR1 cell identity of these CD4+ T cells was supported by their expression of interferon gamma and IL-10, as well as inhibitory receptors including PD-1. TR1 cells with cytotoxic capacity accumulate also in Eµ-TCL1 mice that develop CLL-like disease. Whereas wild-type CD4+ T cells control TCL1 leukemia development after adoptive transfer in leukopenic Rag2−/− mice, EOMES-deficient CD4+ T cells failed to do so. We further show that TR1 cell-mediated control of TCL1 leukemia requires IL-10 receptor (IL-10R) signaling, as Il10rb-deficient CD4+ T cells showed impaired antileukemia activity. Altogether, our data demonstrate that EOMES is indispensable for the development of IL-10-expressing, cytotoxic TR1 cells, which accumulate in LNs of CLL patients and control TCL1 leukemia in mice in an IL-10R-dependent manner.

scholarly journals CD19 CAR T cells following autologous transplantation in poor-risk relapsed and refractory B-cell non-Hodgkin lymphoma

Blood ◽  
2019 ◽  
Vol 134 (7) ◽  
pp. 626-635 ◽  
Author(s):  
Craig S. Sauter ◽  
Brigitte Senechal ◽  
Isabelle Rivière ◽  
Ai Ni ◽  
Yvette Bernal ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
B Cell Lymphoma ◽  
Car T Cells ◽  
Poor Risk ◽  
Car T Cell ◽  
Non Hodgkin Lymphoma ◽  
Car T

Abstract High-dose chemotherapy and autologous stem cell transplantation (HDT-ASCT) is the standard of care for relapsed or primary refractory (rel/ref) chemorefractory diffuse large B-cell lymphoma. Only 50% of patients are cured with this approach. We investigated safety and efficacy of CD19-specific chimeric antigen receptor (CAR) T cells administered following HDT-ASCT. Eligibility for this study includes poor-risk rel/ref aggressive B-cell non-Hodgkin lymphoma chemosensitive to salvage therapy with: (1) positron emission tomography–positive disease or (2) bone marrow involvement. Patients underwent standard HDT-ASCT followed by 19-28z CAR T cells on days +2 and +3. Of 15 subjects treated on study, dose-limiting toxicity was observed at both dose levels (5 × 106 and 1 × 107 19-28z CAR T per kilogram). Ten of 15 subjects experienced CAR T-cell–induced neurotoxicity and/or cytokine release syndrome (CRS), which were associated with greater CAR T-cell persistence (P = .05) but not peak CAR T-cell expansion. Serum interferon-γ elevation (P < .001) and possibly interleukin-10 (P = .07) were associated with toxicity. The 2-year progression-free survival (PFS) is 30% (95% confidence interval, 20% to 70%).  Subjects given decreased naive-like (CD45RA+CCR7+) CD4+ and CD8+ CAR T cells experienced superior PFS (P = .02 and .04, respectively). There was no association between CAR T-cell peak expansion, persistence, or cytokine changes and PFS. 19-28z CAR T cells following HDT-ASCT were associated with a high incidence of reversible neurotoxicity and CRS. Following HDT-ASCT, effector CD4+ and CD8+ immunophenotypes may improve disease control. This trial was registered at www.clinicaltrials.gov as #NCT01840566.

scholarly journals An antigen shared by a human T cell subset and B cell chronic lymphocytic leukemic cells. Distribution on normal and malignant lymphoid cells.

1980 ◽  
Vol 152 (1) ◽  
pp. 229-234 ◽  
Author(s):  
L Boumsell ◽  
H Coppin ◽  
D Pham ◽  
B Raynal ◽  
J Lemerle ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
B Cell ◽  
Cell Subset ◽  
Lymphocytic Leukemia ◽  
Lymphoid Cells ◽  
Antigenic Determinants ◽  
Human T Cell ◽  
Cell Chronic Lymphocytic Leukemia

We obtained a monoclonal antibody, A50, after immunizing Biozzi's high responder strain of mice with T cell chronic lymphocytic leukemia (T-CLL) cells. A50 recognized an antigen present on the surface of B cell chronic lymphocytic leukemia cells from many patients and from cells of T lineage from any subject we tested. We could not find this antigen either on the surface of normal B cell or on other non-T cell malignancies. On T cells, this antigen was present on a subpopulation of thymus cells, and on most peripheral T cells. The antigen was present on the surface of cells from T-CLL, Sézary's disease, and a subset o T cell lymphoma. The antigen seemed to belong to a complex set of antigenic determinants that we had defined with rabbit antisera.

scholarly journals The Feature of Distribution and Clonality of TCRγ/δSubfamilies T Cells in Patients with B-Cell Non-Hodgkin Lymphoma

2014 ◽  
Vol 2014 ◽  
pp. 1-6 ◽  
Author(s):  
Liang Wang ◽  
Meng Xu ◽  
Chunyan Wang ◽  
Lihua Zhu ◽  
Junyan Hu ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Distribution Patterns ◽  
Cell Receptor ◽  
Non Hodgkin Lymphoma ◽  
Clonal Proliferation

Restricted T-cell receptor (TCR) Vα/Vβrepertoire expression and clonal expansion ofαβT cells especially for putative tumor-associated antigens were observed in patients with hematological malignancies. To further characterize theγδT-cell immune status in B-cell non-Hodgkin lymphoma (B-NHL), we investigated the distribution and clonality of TCR Vγ/Vδrepertoire in peripheral blood (PB), bone marrow (BM), and lymph node (LN) from patients with B-NHL. Four newly diagnosed B-NHL cases, including three with diffuse large B-cell lymphoma (DLBCL) and one with small lymphocytic lymphoma (SLL), were enrolled. The restrictive expression of TCR Vγ/Vδsubfamilies with different distribution patterns could be detected in PB, BM, or LN from all of four patients, and partial subfamily T cells showed clonal proliferation. At least one clonally expanded Vδsubfamily member was found in PB from each patient. However, the expression pattern and clonality of TCR Vγ/Vδchanged in different immune organs and showed individual feature in different patients. The clonally expanded Vδ5, Vδ6, and Vδ8 were detected only in PB but neither in BM nor LN while clonally expanded Vδ2 and Vδ3 could be detected in both PB and BM/LN. In conclusion, the results provide a preliminary profile of distribution and clonality of TCRγ/δsubfamilies T cells in PB, BM, and LN from B-NHL; similar clonally expanded Vδsubfamily T cells in PB and BM may be related to the same B-cell lymphoma-associated antigens, while the different reactive clonally expanded Vγ/VδT cells may be due to local immune response.

Engineering Antitumor Immunity by T-Cell Adoptive Immunotherapy

Hematology ◽  
2007 ◽  
Vol 2007 (1) ◽  
pp. 250-256 ◽  
Author(s):  
Stanley R. Riddell
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Viral Infections ◽  
B Cell Lymphoma ◽  
T Cell Therapy ◽  
Memory Pool ◽  
T Cell Transfer

Abstract The adoptive transfer of antigen-specific T cells has been used successfully to treat experimental tumors in animal models and viral infections in humans, but harnessing the exquisite specificity and potency of T cells to treat human malignancy has proven challenging. The efforts to use T cells to treat patients with cancer have often been informative in identifying limitations that must be overcome to improve therapeutic efficacy, and a clearer picture of the requirements for successful adoptive T-cell transfer is gradually emerging. Indolent and a subset of aggressive B-cell lymphomas in humans have been shown to be susceptible to eradication by T cells in clinical settings where highly immunogenic minor histocompatibility or viral antigens are presented by tumor cells. In this article, we will review how recent advances in our understanding of the properties of antigen-specific T cells that facilitate their long-term persistence in vivo and reversion to the memory pool after in vitro culture, combined with approaches to molecularly engineer T cells with receptors that target molecules expressed by B-cell lymphoma, are providing opportunities to broaden the application of T-cell therapy and improve its efficacy for this disease.

CD8+ /ICOS+ /CXCR5+ Tumor Infiltrating T-CELLS (CD8fc) Sharing Functional Similarities With TFH CELLS ARE Present In Classical Hodgkin’S Lymphoma Tissues Displaying A Specific “MIXED NODULARITY” Pattern

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4233-4233 ◽  
Author(s):  
Suong Le Thi ◽  
Florence Broussais ◽  
Reda Bouabdallah ◽  
Françoise gondois-Rey ◽  
Luc Xerri ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Cd8 T Cells ◽  
Cell Lymphoma ◽  
Cell Subset ◽  
B Cell Lymphoma ◽  
Cd8 T Cell ◽  
Tissue Samples ◽  
Tfh Cells

Abstract We have previously reported that some classical Hodgkin’s Lymphoma (cHL) tissues display a gene signature evocative of a Th1 immune reaction. In order to better characterize this process, immune cell subsets were isolated from cHL tissue samples (n=21) using a powerful multicolor flow cytometry method, in parallel with cell sorting. Fresh tissue samples from follicular B cell lymphoma (FL, n=8), diffuse large cell B cell lymphoma (n=8) and reactive lymphadenitis (n= 5) were used as controls. In 4 cLH cases, we observed a significant proportion of activated CD8+ T-cells expressing ICOS and CXCR5 at high levels. The presence of either CD8+/ICOS+/CXCR5- T cells or CD8+/ICOS +/ CXCR5+ T-cells was a specific feature of HL tissues since it was absent from B-cell lymphomas, T-cell lymphomas and reactive tissues. In contrast, CD8+/CXCR5+ T-cells were found not only in cHL, but also in most other samples analyzed. Further phenotypic characterization showed that the CD8+/ICOS +/ CXCR5+ T cells expressed markers associated with CD4 TFH cells, like PD1, BTLA, bcl-6 and IL-21. Under stimulation, they expressed only low levels of IFNG, granzyme B and perforin, and thus do not fulfill the criteria of activated cytotoxic effectors. Co-culture experiments showed a dramatic enhancement of CD86 expression on stimulated B-cells in contact with CD8+/ICOS +/ CXCR5+ T cells. This effect was similarly observed after co-culture with CD4+TFH cells. The 4 cHL cases associated with CD8+/ICOS +/ CXCR5+ T-cells contained CD30+ CD15+ EBV+ Reed Sternberg cells (RSC). They were characterized a nodular non-sclerotic pattern reminiscent of the nodular lymphocyte-rich classical HL (NLRCHL) subtype, but also displayed a specific “mixed nodularity” feature. Various nodules were indeed observed, including reactive germinal centers (GC) partly colonized by RSC co-localizing with CD8+/ICOS+ T-cells, suggesting an early GC invasion triggering an intra-follicular CD8 T-cell reaction. Other nodules were composed of a high number of RS cells admixed with numerous CD8+/ICOS+ T-cells. This “mixed nodularity” pattern was absent in the other HL cases. Altogether, our results point out a previously unrecognized intra- follicular CD8 T-cell subset sharing phenotypic and functional features with CD4 TFH, that we have thus considered as putative “follicular cytotoxic” CD8 T-cells (TFC). This cell subset appears to be specifically associated with EBV+ cHL tissues with unusual histo-phenotypic features, which may probably reflect a strong CD8 activation process. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeting CD38 is lethal to Breg-like chronic lymphocytic leukemia cells and Tregs, but restores CD8+ T-cell responses

2020 ◽  
Vol 4 (10) ◽  
pp. 2143-2157 ◽  
Author(s):  
Alak Manna ◽  
Timothy Kellett ◽  
Sonikpreet Aulakh ◽  
Laura J. Lewis-Tuffin ◽  
Navnita Dutta ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Chronic Lymphocytic Leukemia ◽  
Cd8 T Cells ◽  
Mononuclear Cells ◽  
Transforming Growth Factor ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Lymphocytic Leukemia ◽  
Dependent Manner

Abstract Patients with chronic lymphocytic leukemia (CLL) are characterized by monoclonal expansion of CD5+CD23+CD27+CD19+κ/λ+ B lymphocytes and are clinically noted to have profound immune suppression. In these patients, it has been recently shown that a subset of B cells possesses regulatory functions and secretes high levels of interleukin 10 (IL-10). Our investigation identified that CLL cells with a CD19+CD24+CD38hi immunophenotype (B regulatory cell [Breg]–like CLL cells) produce high amounts of IL-10 and transforming growth factor β (TGF-β) and are capable of transforming naive T helper cells into CD4+CD25+FoxP3+ T regulatory cells (Tregs) in an IL-10/TGF-β-dependent manner. A strong correlation between the percentage of CD38+ CLL cells and Tregs was observed. CD38hi Tregs comprised more than 50% of Tregs in peripheral blood mononuclear cells (PBMCs) in patients with CLL. Anti-CD38 targeting agents resulted in lethality of both Breg-like CLL and Treg cells via apoptosis. Ex vivo, use of anti-CD38 monoclonal antibody (mAb) therapy was associated with a reduction in IL-10 and CLL patient-derived Tregs, but an increase in interferon-γ and proliferation of cytotoxic CD8+ T cells with an activated phenotype, which showed an improved ability to lyse patient-autologous CLL cells. Finally, effects of anti-CD38 mAb therapy were validated in a CLL–patient-derived xenograft model in vivo, which showed decreased percentage of Bregs, Tregs, and PD1+CD38hiCD8+ T cells, but increased Th17 and CD8+ T cells (vs vehicle). Altogether, our results demonstrate that targeting CD38 in CLL can modulate the tumor microenvironment; skewing T-cell populations from an immunosuppressive to immune-reactive milieu, thus promoting immune reconstitution for enhanced anti-CLL response.

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