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

Abstract

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...

The novel immunosuppressive enzyme IL4I1 is expressed by neoplastic cells of several B-cell lymphomas and by tumor-associated macrophages

“…Involvement of IL4 in follicular lymphoma pathogenesis has been recently reported, along with Erk and STAT6 activation. 21 However, we could not correlate expression of the immunoglobulin E receptor CD23, a STAT6 target, by tumor cells, with IL4I1 expression (data not shown). In cHL and follicular lymphoma, IL4I1 might thus be induced by other signals in addition to the IL4/IL13/ STAT6 pathway.…”

Elevated serum levels of IL-2R, IL-1RA, and CXCL9 are associated with a poor prognosis in follicular lymphoma

“…IL-4 has been reported to be elevated in FL with downstream phosphorylation of Erk and activation of Mek. 38 Gene expression profiling has made inroads by demonstrating activation of IL-4-dependent activation of STAT6 in FL B cells and T-helper cells in the tumor microenvironment indicating an interdependent axis. 39 IL-10 and Leptin have been associated with FL development and result in immune suppression.…”

MicroRNA profiling of follicular lymphoma identifies microRNAs related to cell proliferation and tumor response

“…4 Additional molecular lesions or secondary hits are required to cooperate with BCL2 in the evolution of the malignant phenotype, although the precise mechanisms of lymphomagenesis remain to be elucidated. Gene expression profile studies of FL further suggest that the lymph node microenvironment may play a role in the biology of FL through tumor infiltrating T cells and macrophages, [5][6][7][8][9] possibly involving cytokines 10,11 or other immunomodulatory mechanisms.…”

“…We previously reported that IL-4 protein is increased, and MAPK1 is activated in FL, as determined by multiplex cytokine ELISA arrays and reverse-phase protein arrays. 11 One recent study identified the source of increased IL-4 expression in FL as tumor-infiltrating T helper cells, with the consequence of over-expression of IL-4-regulated genes in FL tumor cells via activation of STAT6. 10 In our current study, we found increased expression of IL4R, MAPK1 and AKT transcripts in enriched sorted FL tumor cells, further indicating that IL4/IL4R, MAPK and PI-3K/AKT pathways potentially play crucial roles in FL tumor proliferation and survival.…”