T‐cell derived cytokines co‐stimulate proliferation of CD40‐activated germinal centre as well as follicular lymphoma cells

Schmitter, Doris; Koss, Michael; Niederer, Eva; Stahel, Rolf A.; Pichert, Gabriella

doi:10.1002/(sici)1099-1069(199711)15:4<197::aid-hon614>3.3.co;2-m

Cited by 12 publications

(13 citation statements)

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“…However, to complicate the picture, IL-21 also activates CTLs and NK cells, and antitumoral effects of IL-21 (including apoptosis of follicular lymphoma cell lines) have been seen (23). Helper T cells, and T FH most proficiently, express CD40L, which protects follicular lymphoma cells from apoptosis through CD40 (24), and other signals, such as IL-4, stimulating the follicular lymphoma cells to proliferate (25,26). Tregs, defined as FOXP3 + (27), have been associated with good prognosis in follicular lymphoma (8,9,18).…”

Section: Discussionmentioning

confidence: 99%

A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1–Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages

Wahlin

Aggarwal

Montes‐Moreno

et al. 2010

Clinical Cancer Research

158

164

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Purpose: The microenvironment influences outcome in follicular lymphoma. Our hypothesis was that several immune cell subsets are important for disease outcome and their individual prognostic importance should be demonstrable in the same analysis and in competition with clinical factors.Experimental Design: Seventy follicular lymphoma patients with extreme clinical outcome ("poor" and "good" cases) were selected in a population-based cohort of 197. None of the 37 good-outcome patients died from lymphoma, whereas all the 33 poor-outcome patients succumbed in ≤5 years. Furthermore, the good-outcome patients were followed for a long time and needed no or little treatment. A tissue microarray was constructed from diagnostic, pretreatment biopsies. Cellular subsets were quantified after immunostaining, using computerized image analysis, separating cells inside and outside the follicles (follicular and interfollicular compartments). Flow cytometry data from the same samples were also used.Results: Independently of the Follicular Lymphoma International Prognostic Index, CD4 + cells were associated with poor outcome and programmed death-1-positive and CD8 + cells were associated with good outcome. The prognostic values of CD4 + and programmed death-1-positive cells were accentuated when they were follicular and that of CD8 + cells were accentuated when they were interfollicular. Follicular FOXP3 + cells were associated with good outcome and interfollicular CD68 + cells were associated with poor outcome. Additionally, high CD4/CD8 and CD4 follicular/interfollicular ratios correlated with poor outcome. Conclusion: There are many important immune cell subsets in the microenvironment of follicular lymphoma. Each of these is independently associated with outcome. This is the first study showing the effect of the balance of the entire microenvironment, not only of individual subsets.

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Section: Discussionmentioning

confidence: 99%

A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1–Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages

Wahlin

Aggarwal

Montes‐Moreno

et al. 2010

Clinical Cancer Research

158

164

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“…49 In addition, a previous report demonstrated that IL-4 slightly and irregularly enhanced the proliferation of FL B cells in vitro. 50 In our study, we highlighted a strong anti-apoptotic activity of CD40L and IL-4 on FL B cells treated in vitro with rituximab. Interestingly, this anti-apoptotic effect was inversely correlated to the sensitivity of malignant FL B cells to rituximab.…”

Section: Discussionmentioning

confidence: 99%

Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells

et al. 2011

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Accumulating evidences indicate that the cellular and molecular microenvironment of follicular lymphoma (FL) has a key role in both lymphomagenesis and patient outcome. Malignant FL B cells are found admixed to specific stromal and immune cell subsets, in particular CD4 pos T cells displaying phenotypic features of follicular helper T cells (T FH ). The goal of our study was to functionally characterize intratumoral CD4 pos T cells. We showed that CXCR5 hi ICOS hi CD4 pos T cells sorted from FL biopsies comprise at least two separate cell populations with distinct genetic and functional features: (i) CD25 pos follicular regulatory T cells (T FR ), and (ii) CD25 neg T FH displaying a FL-B cell supportive activity without regulatory functions. Furthermore, despite their strong similarities with tonsil-derived T FH , purified FL-derived T FH displayed a specific gene expression profile including an overexpression of several genes potentially involved directly or indirectly in lymphomagenesis, in particular TNF, LTA, IL4 or CD40LG. Interestingly, we further demonstrated that these two last signals efficiently rescued malignant B cells from spontaneous and rituximab-induced apoptosis. Altogether, our study demonstrates that tumor-infiltrating CD4 pos T cells are more heterogeneous than previously presumed, and underlines for the first time the crucial role of T FH in the complex set of cellular interactions within FL microenvironment.

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“…FL cells are reported to up-regulate the IL-4 receptor ␣. 40 In addition, IL-4 has been demonstrated to be a potent stimulator of FL cell proliferation in vitro, 37 and Erk is an established regulator of proliferation within the MAP kinase pathway. 45 Further studies are needed to elucidate the roles of IL-4 and Erk in FL.…”

Section: Discussionmentioning

confidence: 99%

IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma

Calvo

Dabir

Kovach

et al. 2008

Blood

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IntroductionFollicular lymphoma (FL) is a non-Hodgkin lymphoma of germinal center B-cell origin. FL is the second most common nonHodgkin lymphoma and represents 20% of all lymphomas in the adult population. 1 Although the course of disease is indolent, it is largely incurable, with a median survival of 7 to 10 years. With time, FL typically transforms into a high-grade lymphoma. FL is characterized by the t(14;18) (q32;q21) translocation, 2-4 which leads to constitutive expression of the antiapoptotic Bcl-2 protein, conferring survival advantage to FL cells. 5 The BCL-2/JH translocation is required but not sufficient for lymphomagenesis, underscored by the fact that the BCL2/JH translocation has been identified in B cells from lymph nodes (LNs) and blood in healthy individuals. 6,7,8 Hence, there are likely other genetic alterations within tumor cells that cooperate with Bcl-2 to drive the malignant phenotype in FL.There is compelling evidence that FL tumor cells are dependent upon the LN microenvironment for continued survival and proliferation. [9][10][11] Two distinct gene expression signatures that predict patient survival independent of clinical prognostic variables have been identified by gene expression profiling. 11 The expression profile designated immune response 1 (IR1) includes T cell-and macrophage-restricted genes and was predictive of a favorable clinical outcome. In contrast, IR2 is associated with genes primarily expressed by monocytes and dendritic cells and was predictive of a poorer outcome. Other studies have also implicated the importance of the tumor-host microenvironment in FL. Patients with spontaneous regression of FL reportedly demonstrated increased numbers of T-helper cells with no apparent differences in cytotoxic T cells or macrophages when compared with patients with FL exhibiting no regression. 9 Increased numbers of CD57 ϩ T cells have been associated with a higher frequency of B symptoms and bone marrow involvement. 12 The presence of high numbers of CD68 ϩ macrophages (Ͼ 15 per high-power field) was an independent negative predictor of survival in one study. 13 Intratumoral T cells and macrophages presumably exert effects on the FL microenvironment via secretion of cytokines and/or by direct interaction with tumor cells. Studies have shown FL cells to proliferate in vitro in the presence of autologous CD4 ϩ T cells, 14 and in the presence of CD4 ϩ T-cell clones that recognize alloantigens expressed by FL cells. 10 Polymorphisms of several cytokines have been implicated in susceptibility to non-Hodgkin lymphoma, including tumor necrosis factor (TNF) and interleukin-10 (IL-10). 15 Single-nucleotide polymorphisms (SNPs) of IL-8, IL-2, IL-12␤, and the IL-1 receptor were shown in one study to be predictive of survival in patients diagnosed with FL. 16 Cytokines play key roles in the regulation of hematopoietic differentiation, proliferation, and apoptosis. Cytokines commonly trigger signal transduction in target cells via the Janus kinase (Jak)-signal transducer and activator of tr...

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T‐cell derived cytokines co‐stimulate proliferation of CD40‐activated germinal centre as well as follicular lymphoma cells

Cited by 12 publications

References 0 publications

A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1–Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages

A Unifying Microenvironment Model in Follicular Lymphoma: Outcome Is Predicted by Programmed Death-1–Positive, Regulatory, Cytotoxic, and Helper T Cells and Macrophages

Characterization of intratumoral follicular helper T cells in follicular lymphoma: role in the survival of malignant B cells

IL-4 protein expression and basal activation of Erk in vivo in follicular lymphoma

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