Allergic TH2 Response Governed by B-Cell Lymphoma 6 Function in Naturally Occurring Memory Phenotype CD4+ T Cells

Background. Diffuse large B-cell lymphoma (DLBCL) is a clinically and genetically heterogeneous lymphoid malignancy. The unsatisfactory outcome for refractory patients has prompted efforts to explore new therapeutic approaches for DLBCL. However, the mechanisms involved in treatment associated with immune checkpoints remain unclear. This study is aimed at investigating the potential roles of programmed cell death protein 1 (PD1) and lymphocyte activation gene 3 (LAG3) in CD8+ T cells for treatment in DLBCL. Methods. Utilizing flow cytometry, we examined the content of T cells, the levels of cytokines, and the expression of PD1 and LAG3 in patients with DLBCL as well as in healthy controls. Levels of cytokines in CD8+ T cells from DLBCL patients before and after treatment were compared by blocking of PD1 and LAG3 in magnetic bead-sorted CD8+ T cells. Results. We found that the proportion of CD4+ T cells and CD8+ T cells was increased in DLBCL patients after treatment. The levels of cytokines trended toward those of healthy controls in treatment. PD1 (+), LAG3 (+), or PD1 (+) LAG3 (+) were all expressed in lower amounts in CD4+ T cells and CD8+ T cells after treatment than in untreated DLBCL patients. In addition, blockade of PD1 and LAG3 in sorted CD8+ T cells markedly inhibited cytokine production in response to treatment. Conclusion. PD1 and LAG3 in CD8+ T cells may be important targets of therapy and play therapeutic role in patients with DLBCL.

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Depot Formulation of Interleukin-2 as an Immunotheraphy for B-Cell Lymphoma.

Blood ◽

10.1182/blood.v110.11.1398.1398 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1398-1398

Author(s):

Sofia Grille ◽

Andreina Brugnini Lic ◽

Esteban Corley ◽

Martha Nese ◽

Jose Alejandro Chabalgoity ◽

...

Keyword(s):

Flow Cytometry ◽

T Cells ◽

B Cell ◽

Tumor Cells ◽

Cd4 T Cells ◽

Cell Lymphoma ◽

Interleukin 2 ◽

B Cell Lymphoma ◽

Treg Cells ◽

Depot Formulation

Abstract Relapses occurring in most lymphoma patients after treatment highlight the need for effective immunotheraphy approaches. Induction of tumor-specific adaptive immunity in cancer patients is an ideal approach because its selectivity and memory for the same tumors eventually prevent the relapse after conventional therapies. Vaccination with cytokines and tumor cells represents an attractive therapeutic approach for patients with B-cell lymphoma. Interleukin-2 (IL-2) has a wide range of immunologic effects, including the activation of cytotoxic T cells and natural killer cells (NK). The therapeutic use of IL-2 has generated substantial interest based on its ability to induce the regression of metastatic renal cell carcinomas and malignant melanomas tumors in humans. However, toxicity associated with systemic administration of large doses of cytokine is a major drawback for clinical application. In this work, we investigated whether in vivo vaccination with a cytokine-based immunotherapy using IL-2 adsorbed in alum, as a depot system, with lysed lymphoma cells could stimulate lymphoma-specific immunity and improve survival. We developed a reproducible syngenic model of B-cell lymphoma in Balb/c mouse based upon the A20 cell line. In this model animals died between day 35 and 40 after tumor cells inoculation. Mice were first injected subcutaneously with 1 x 106 A20 cell in right flank. Four groups of mice received at days 3 and 7 after tumor cell inoculation by subcutaneous injections one of the following: lysed A20 cells with IL-2 in alumn (A20-IL-2); Lysed A20 cells in alumn (A20); IL-2 in alumn (IL-2); and phosphate-buffered saline (PBS) as control. Mice were followed for survival and immune response was evaluated. At day 22, 17% of A20-IL-2 group had systemic disseminated disease in comparison with 33% A20 group, 83% for IL-2 group and 100% of PBS group (p=0.009). Mice vaccinated with A20-IL-2 had longer survival compared with mice vaccinated with A20 or PBS (p=0.0019). Prolonged survival was related with a marked increase in the number of intratumoral CD4+ T cells (p=0.0001), CD8+ T cells (p=0.001) and NK cells (p=0.001). Aditionally, at day 22 groups of mice vaccinated with A20 showed a significantly lower percentages of intratumoral CD4+ CD25+ CD127- Treg cells in the tumor as compared with PBS group (p=0.0001). At day 39 the percentage of intratumoral Treg cells increased in the groups vaccinated with IL-2 (A20-IL-2 and IL-2 groups). Intratumoral CD4+, CD8+, NK and Treg cells were evaluated by flow cytometry. Interestingly, intracellular cytokine analysis showed a greater number of intratumoral INF-γ producing CD4+ T cells in mice vaccinated with A20-IL-2. Proliferation assays by flow cytometry (using carboxy-fluorescein diacetate, succinimidyl ester and propidium iodide) showed enhanced proliferation upon stimulation with irradiated A20 cells in splenocytes from A20-IL-2 vaccinated mice (p=0.004). In conclusion, the results of this study indicate that vaccination with A20 antigens combined with a depot formulation of IL-2 elicits strong anti-tumor specific immunity and extended survival. This approach may be an interesting strategy to promote systemic immunity against B-cell lymphoma with therapeutic value.

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Predominance of CD4+ T Cells in T-Cell/Histiocyte-Rich Large B-Cell Lymphoma and Identification of a Subset of Patients With Peripheral B-Cell Lymphopenia

American Journal of Clinical Pathology ◽

10.1093/ajcp/aqx034 ◽

2017 ◽

Vol 147 (6) ◽

pp. 596-603 ◽

Cited By ~ 7

Author(s):

Christian Kunder ◽

Michael J. Cascio ◽

Anthony Bakke ◽

Girish Venkataraman ◽

Dennis P. O’Malley ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Cd4 T Cells ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Therapeutic effect of idiotype-specific CD4+ T cells against B-cell lymphoma in the absence of anti-idiotypic antibodies

Blood ◽

10.1182/blood-2002-11-3381 ◽

2003 ◽

Vol 102 (2) ◽

pp. 605-612 ◽

Cited By ~ 26

Author(s):

Katrin U. Lundin ◽

Peter O. Hofgaard ◽

Hilde Omholt ◽

Ludvig A. Munthe ◽

Alexandre Corthay ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd4 T Cells ◽

Cell Lymphoma ◽

Severe Combined Immunodeficiency ◽

Tumor Development ◽

B Cell Lymphoma ◽

Lymphoma Cells ◽

B Lymphoma ◽

B Lymphoma Cells

AbstractImmunoglobulin (Ig) variable (V) region idiotypes (Id's) are highly tumor-specific antigens produced by B-lymphoma cells and are promising targets for immunotherapy. Id vaccination has proven effective in experimental mouse models and may possibly prevent recurrence of B lymphomas in humans. It has previously been shown that anti-Id antibodies protect against B-cell lymphoma in the absence of T cells. We here demonstrate in a T-cell–receptor transgenic mouse model that the contrary is also true: Id-specific CD4+ T cells can protect against Id+ B-lymphoma cells in the absence of B cells, antibodies, and CD8+ T cells. Moreover, Id-specific CD4+ T cells have a curative potential since they could be transferred as late as 17 days after subcutaneous tumor cell injection of severe combined immunodeficiency (SCID) mice and still abrogate tumor development in about 50% of mice. Such mice undergo an acute inflammatory swelling with infiltration of neutrophils at the site of tumor injection, which subsides over weeks, with some mice cured and delayed emergence of lymphomas in other mice. Adoptively transferred CD4+ T cells accumulated in the tumor and were activated (CD69+). In vitro experiments demonstrated that memory, but not naive, Id-specific CD4+ T cells kill Id+ B-lymphoma cells. The results show that Id-specific CD4+ T cells, in the absence of antibodies home to subcutaneous Id+ B lymphoma, become activated, induce inflammation, and prevent tumor development.

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Polyfunctional CD4+ T cells are essential for eradicating advanced B-cell lymphoma after chemotherapy

Blood ◽

10.1182/blood-2011-12-398321 ◽

2012 ◽

Vol 120 (11) ◽

pp. 2229-2239 ◽

Cited By ~ 51

Author(s):

Zhi-Chun Ding ◽

Lei Huang ◽

Bruce R. Blazar ◽

Hideo Yagita ◽

Andrew L. Mellor ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd4 T Cells ◽

Antitumor Immunity ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Chemotherapeutic Agents ◽

Late Relapse ◽

Antitumor Effects ◽

Effector Cells

Abstract The finding that many chemotherapeutic agents have immunostimulatory effects has provided the impetus to combine chemotherapy and immunotherapy for synergistic antitumor effects. However, the critical determinants of effective antitumor immunity after chemotherapy have not been defined. Here we report that adoptive transfer of tumor-specific CD4+ T cells after chemotherapy with cyclophosphamide gave rise to polyfunctional CD4+ effector cells, which in turn intensified the inflammatory milieu and enhanced the activation of CD8+ T cells in the tumor microenvironment. Although this combined chemoimmunotherapy initially resulted in progressive regression of advanced B-cell lymphoma, its therapeutic efficacy was not durable and most mice succumbed to late relapse. Notably, relapse was associated with acquisition of a tolerized phenotype in tumor-specific CD4+ T cells, characterized by overexpression of program death-1 (PD-1). Remarkably, effective antitumor immunity was maintained and cure became prevalent when polyfunctional CD4+ effector cells were prevented from undergoing PD-1–mediated tolerization, either by antibody blockade of the PD-1–PD-L1 pathway, or targeted ablation of PD-1 in tumor-specific CD4+ T cells. Our study suggests that tumor-reactive CD4+ T cells act as the “gatekeepers” of the host antitumor immunity in the postchemotherapy setting, thereby their functional status governs the choice between eradication versus regrowth of residual tumors.

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Thymic hyperplasia after chemotherapy in adults with mature B cell lymphoma and its influence on thymic output and CD4+T cells repopulation

OncoImmunology ◽

10.1080/2162402x.2015.1137417 ◽

2016 ◽

Vol 5 (5) ◽

pp. e1137417 ◽

Cited By ~ 5

Author(s):

Dao-Ping Sun ◽

Hui Jin ◽

Chong-Yang Ding ◽

Jin-Hua Liang ◽

Li Wang ◽

...

Keyword(s):

T Cells ◽

B Cell ◽

Cd4 T Cells ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Thymic Hyperplasia ◽

Thymic Output

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Orphan designation: Autologous CD4+ and CD8+ T cells expressing a CD19-specific chimeric antigen receptor, Treatment of diffuse large B-cell lymphoma

Case Medical Research ◽

10.31525/cmr-beb833 ◽

2019 ◽

Author(s):

Keyword(s):

T Cells ◽

B Cell ◽

Chimeric Antigen Receptor ◽

Cd8 T Cells ◽

Cell Lymphoma ◽

Antigen Receptor ◽

B Cell Lymphoma ◽

Orphan Designation ◽

Large B Cell Lymphoma ◽

Large B Cell

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

Blood Cancer Journal ◽

10.1038/s41408-020-00404-0 ◽

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.

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