Citations

AbstractStromal elements present within the tumor microenvironment may suppress host immunity and promote the growth of malignant lymphocytes in B cell–derived non-Hodgkin lymphoma (NHL). In contrast, little is known about the microenvironment's role in T cell–derived NHL. B7-H1 (PD-L1, CD274), a member of the B7 family of costimulatory/coinhibitory ligands expressed by both malignant cells and stromal cells within the tumor microenvironment, has emerged as an important immune modulator capable of suppressing host immunity. Therefore, B7-H1 expression and function were analyzed in cutaneous and peripheral T-cell NHL. B7-H1 was expressed by tumor cells, monocytes, and monocyte-derived cells within the tumor microenvironment in T-cell NHL and was found to inhibit T-cell proliferation and promote the induction of FoxP3+ regulatory T cells. Collectively, the data presented provide the first evidence implicating B7-H1 in the suppression of host immunity in T-cell lymphoproliferative disorders and suggest that the targeting of B7-H1 may represent a novel therapeutic approach.

Abstract Using biopsy specimens from patients with B-cell non-Hodgkin's lymphoma, we observed a significantly low frequency of TH17 cells, including several samples with no detectable amount of interleukin (IL)-17–producing cells present in the tumor microenvironment. We found that, in the absence of lymphoma B cells, treatment with IL-1β/IL-6 or lipopolysaccharide (LPS) enhanced IL-17 expression in CD4+ T cells and this enhancement was attenuated when CD4+ T cells were cocultured with lymphoma B cells. Blockade of CD27-CD70 or CD28-CD80/86 interactions by anti-CD70 or anti-CD80/86 antibodies restored LPS-mediated induction of IL-17 expression in CD4+ T cells cocultured with lymphoma B cells. Because a subset of lymphoma B cells express IL-2 and given that IL-2 signaling is critically important in the development of regulatory T (Treg) cells, we tested the role of IL-2 signaling in TH17 cell development. We found that treatment with anti-IL-2 antibody to interrupt IL-2 signaling significantly inhibited Foxp3 expression in CD4+ T cells. In contrast, interruption of IL-2 signaling up-regulated IL-17 expression in CD4+ T cells and restored lymphoma-mediated down-regulation of IL-17–producing cells. Furthermore, the reversal of Treg cell activity by LPS or CpG-A resulted in an enhancement of IL-17–producing cells. Taken together, our study indicated that lymphoma B cells play an important role in skewing the balance between Treg and TH17 cells resulting in the establishment of a profoundly inhibitory tumor microenvironment. [Cancer Res 2009;69(13):5522–30]

Abstract Elevated B-cell–activating factor (BAFF; TNFSF13B) levels have been found in patients with B-cell malignancies and autoimmune diseases, suggesting that it may play a pathogenic role. We previously found that a single nucleotide polymorphism (SNP) in the TNFSF13B promoter resulted in increased transcription, suggesting that genetic variation in TNFSF13B may influence its expression. We therefore wanted to determine if genetic variation in TNFSF13B is associated with high BAFF levels and non–Hogkin lymphoma (NHL) risk. We genotyped 9 tagSNPs within TNFSF13B in a clinic-based study of 441 NHL cases and 475 matched controls and evaluated the association of individual SNPs with risk of NHL; 3 tagSNPs were significant (P < 0.05). When categorized into low-, moderate-, and high-risk groups based on risk alleles, we found the permutation-corrected odds ratio for the trend to be 1.43 (P = 0.0019) for risk of B-cell NHL, 1.69 (P = 0.0093) for diffuse large B-cell lymphoma, 1.43 (P = 0.029) for follicular lymphoma, and 1.06 (P = 0.21) for chronic lymphocytic leukemia/small lymphocytic lymphoma. The mean serum BAFF level in those who carried the low-risk alleles was 2 ng/mL compared with 4.3 ng/mL in those with the high-risk alleles (P = 0.02). Taken together, our data suggest that genetic variation in the TNFSF13B gene is significantly associated with NHL risk and elevated serum BAFF levels. [Cancer Res 2009;69(10):4217–24]

Abstract A proliferation-inducing ligand (APRIL), as well as its receptors transmembrane activator and calcium-modulating cyclophilin ligand (CAML) interactor (TACI) and B-cell maturation antigen (BCMA), has been shown to be important in B-cell biology, and overexpression of APRIL in mice results in development of lymphoma. Limited data are available on APRIL-specific signaling responses, but knockout models suggest that signaling through TACI is critical to B-cell homeostasis. To better understand the mechanism by which APRIL exerts its effects and how it may contribute to lymphomagenesis, we sought to characterize the outcome of APRIL-TACI interactions. In support of murine studies, we find that APRIL induces proliferation of human patient follicular lymphoma (FL) B cells in a TACI-dependent manner. This study also shows that APRIL is expressed within the tumor microenvironment and that, upon engagement with TACI, APRIL mediates activation of the phosphatidylinositol 3-kinase (PI3K) pathway. Activation of PI3K via APRIL results in phosphorylation of Akt and mammalian target of rapamycin (mTOR) and the mTOR-specific substrates p70S6 kinase and 4E-binding protein 1 in a TACI-dependent manner. APRIL-mediated signaling also results in phosphorylation of Rb and up-regulation of cyclin D1. These studies are the first to characterize APRIL-TACI–specific signaling and suggest a role for this ligand-receptor pair in FL B-cell growth.

Abstract Non-Hodgkin's lymphoma (NHL) is a cancer closely associated with immune function, and the tumor necrosis factor (TNF) G-308A promoter polymorphism, which influences immune function and regulation, was recently reported by the InterLymph Consortium to be associated with NHL risk. TNF signaling activates the nuclear factor-κB (NF-κB) canonical pathway, leading to transcriptional activation of multiple genes that influence inflammation and immune response. We hypothesized that, in addition to TNF signaling, common genetic variation in genes from the NF-κB canonical pathway may affect risk of NHL. We genotyped 54 single nucleotide polymorphisms (SNP) within TNF, lymphotoxin A LTA, and nine NF-κB genes from the canonical pathway (TNFRSF1A, TRADD, TRAF2, TRAF5, RIPK1, CHUK, IKBKB, NFKB1, and REL) in a clinic-based study of 441 incident cases and 475 frequency-matched controls. Tagging SNPs were selected from HapMap supplemented by putative functional SNPs for LTA/TNF. We used principal components and haplo.stats to model gene-level associations and logistic regression to model SNP-level associations. Compared with the wild-type (GG), the AA genotype for the TNF promoter polymorphism G-308A (rs1800629) was associated with increased risk of NHL [odds ratio (OR), 2.14; 95% confidence interval (95% CI), 0.94-4.85], whereas the GA genotype was not (OR, 1.00; 95% CI, 0.74-1.34). This association was similar for follicular lymphoma and diffuse large B-cell lymphoma. A previously reported LTA/TNF haplotype was also associated with NHL risk. In gene-level analysis of the NF-κB pathway, only NFKB1 showed a statistically significant association with NHL (P = 0.049), and one NFKB1 tagSNP (rs4648022) was associated with NHL risk overall (ordinal OR, 0.59; 95% CI, 0.41-0.84; Ptrend = 0.0037) and for each of the common subtypes. In conclusion, we provide additional evidence for the role of genetic variation in TNF and LTA SNPs and haplotypes with risk of NHL and also provide some of the first preliminary evidence for an association of genetic variation in NFKB1, a downstream target of TNF signaling, with risk of NHL. (Cancer Epidemiol Biomarkers Prev 2008;17(11):3161–9)

Abstract Purpose: B-lymphocyte stimulator and a proliferation-inducing ligand regulate B-cell homeostasis and immunoglobulin production and are overexpressed in B-cell malignancies. Atacicept (TACI-Ig), a recombinant fusion protein that inhibits both B-lymphocyte stimulator and a proliferation-inducing ligand, may be a novel treatment for B-cell malignancies. Experimental Design: A phase 1, open-label, dose-escalation study of atacicept in patients with relapsed or refractory B-cell lymphoma was done. Atacicept was given s.c. weekly for 5 weeks to sequential patient cohorts at doses of 2, 4, 7, or 10 mg/kg. Patients responding or with stable disease were eligible for treatment on an extension study for up to 24 weeks or until disease progression. Results: All patients were heavily pretreated (median number of previous treatments, 5; range, 1-10), and four patients had previously received a stem cell transplant. Four patients were treated at the 2, 4, or 7 mg/kg dose levels, and three patients received 10 mg/kg of atacicept. Atacicept was well tolerated at all doses. Three adverse events with grade 3 severity were reported for one patient, including jaw pain, gastrointestinal hemorrhage, and sepsis; all were considered unrelated to atacicept. Pharmacokinetic results were nonlinear, and treatment with atacicept resulted in dose-dependent decreases in immunoglobulin concentrations. Two patients had stable disease at 8 weeks, entered the extension study, and received additional doses of atacicept with no safety or tolerability concerns. Conclusion: Atacicept at doses of up to 10 mg/kg was well tolerated and showed biological activity by decreasing immunoglobulin concentrations, although tumor responses were not observed.

Activation of γ-aminobutyric acid (GABA) A receptors in the suprachiasmatic nucleus (SCN) resets the circadian clock during the day and inhibits the ability of light to reset the clock at night. Light in turn acts during the day to inhibit the phase-resetting effects of GABA. Some evidence suggests that Period mRNA changes in the SCN are responsible for these interactions between light and GABA. Here, the hypothesis that light and the GABA A receptor interact by altering the expression of Period 1 and/or Period 2 mRNA in the SCN is tested. The GABA A agonist muscimol was injected near the SCN just prior to a light pulse, during the mid-subjective day and the early and late subjective night. Changes in Period 1 and Period 2 mRNA were measured in the SCN by in situ hybridization. Light-induced Period 1 mRNA was inhibited by GABA A receptor activation in the early and late subjective night, while Period 2 mRNA was only inhibited during the late night. During the subjective day, light had no effect on the ability of muscimol to suppress Period 1 mRNA hybridization signal. Thus, light and GABA A receptor activation inhibit each other's ability to induce behavioral phase shifts throughout the subjective day and night. However, only in the late night are these behavioral effects correlated with changes in Period gene expression. Together, our data support the hypothesis that the interacting effects of light and GABA are the result of the opposing actions of these stimuli on Period mRNA, but only during the subjective night.

Foxp3 expression was initially thought to be restricted to the CD4+CD25+ regulatory T-cell population. However, recent studies suggest that forkhead box P3 (Foxp3) is expressed in CD4+CD25− T cells in aged mice. In the present study in B-cell non-Hodgkin lymphoma (NHL), we found that a subset of intratumoral but not peripheral blood CD4+CD25− T cells, comprising about 15% of intratumoral CD4+ T cells, express Foxp3 and are capable of suppressing the proliferation of autologous infiltrating CD8+ T cells. In vitro activation with OKT3/anti-CD28 antibody (Ab) or dendritic cells (DCs) induced Foxp3 expression in a subset of these CD4+CD25−Foxp3− T cells. We found that the presence of lymphoma B cells during activation augmented activation-induced Foxp3 expression in CD4+CD25− T cells. We also found that CD70+ lymphoma B cells significantly contributed to the activation-induced Foxp3 expression in intratumoral CD4+CD25− T cells. Furthermore, the blockade of CD27-CD70 interaction by anti-CD70 Ab abrogated lymphoma B-cell–mediated induction of Foxp3 expression in intratumoral CD4+CD25− T cells. Taken together, these studies reveal a novel role for NHL B cells in the development of intratumoral regulatory T cells.

ABSTRACT Obesity is one of the major health problems of our times. Elucidating the signaling mechanisms by which high‐fat caloric diet induces obesity is critical for the understanding of this condition and for the development of therapeutic strategies for its treatment. Here, we demonstrate a novel role for protein CD38 as a regulator of body weight during a high‐fat diet. CD38 is a ubiquitous enzyme that catalyzes the synthesis of second messengers and has been implicated in the regulation of a wide variety of signaling pathways. We report that CD38‐deficient mice are pro‐tected against high‐fat diet‐induced obesity owing to enhanced energy expenditure. In fact, calorimetric studies indicate that CD38‐deficient animals have a higher metabolic rate compared to control mice. Analysis of the mechanism revealed that this resistance to diet‐induced obesity is mediated at least in part via a NAD‐dependent activation of SIRT‐PGC1α axis, a well‐established cascade, involved in the regulation of mito‐chondrial biogenesis and energy homeostasis. Thus, together these results identify a novel pathway regulating body weight and clearly show that CD38 is a nearly obligatory component of the cellular cascade that led to diet‐induced obesity.—Barbosa, M. T. P., Soares, S. M., Novak, C. M., Sinclair, D., Levine, J. A., Aksoy, P., Chini, E. N. The enzyme CD38 (a NAD glycohydrolase, EC 3.2.2.5) is necessary for the development of diet‐induced obesity. FASEB J. 21, 3629–3639 (2007)