For effective immunotherapy, maintaining the frequency and cytotoxic potential of effector cells is critical. In this context costimulation via the CD70/CD27 pathway has been proven essential. CD70 has been reported to be expressed to varying degrees on malignant B cells. However, in B cell precursor acute lymphboblastic leukemia, the most common childhood malignancy, the role of CD70 in stimulation of antileukemic T cell responses has so far not been delineated. Herein we demonstrate that in B cell precursor acute lymphboblastic leukemia expression of CD70 is low but can be induced upon blast activation via CD40. Both CD70 and CD80/CD86 up-regulated on CD40-stimulated blasts contribute to primary stimulation of T cell proliferation and cytokine production in an additive manner. These two signals also cooperate in the prevention of T cell anergy. In contrast to blockade of CD70 during the effector phase, inhibition of CD70-mediated costimulation during generation of antileukemic T cells prevents effector cell proliferation and reduces their cytotoxic capacity. Modulation of the CD70/CD27 pathway may thus represent a novel therapeutic approach for augmenting magnitude and quality of the antileukemic response in B cell precursor acute lymphboblastic leukemia.
Previous studies on apoptosis defects in acute lymphoblastic leukemia (ALL) have focused on chemotherapy-induced, primarily mitochondrial death pathways. Yet, immunologic surveillance mechanisms including sensitization to apoptotic signals mediated via the death receptor CD95 might contribute to leukemic control. Here, we show that primary B-cell precursor ALL cells from children escape from receptor-dependent cell death in 2 ways:Resting ALL blasts are protected from receptor-mediated apoptosis due to the absence of CD95 surface expression. However, even though CD40 ligation results in up-regulation of CD95, ALL blasts, unlike normal B cells, remain resistant to apoptosis. We show that this apoptosis resistance involves the selective upregulation of the short isoforms of the caspase-8 inhibitor c-FLIP acting directly at the CD95 receptor level. IntroductionAcute lymphoblastic leukemia (ALL) in children is a malignant disease with a good overall prognosis. Treatment failure in those patients who suffer relapse has to a large part been attributed to drug resistance and defects in apoptosis. Consequently, investigations on the deregulation of apoptosis in ALL have primarily focused on chemotherapy-induced pathways. 1,2 Yet immunologic surveillance also contributes to long-term survival. 3,4 The capacity of mature normal B cells to respond to CD40 ligation by up-regulation of the CD95 (Fas/APO1) death receptor is critical for their susceptibility to immunologic control. 5-7 Primary B-cell precursor ALL blasts (BCP-ALLs) lack CD95 expression and are resistant to CD95-mediated cell death. 8 Although BCP-ALL blasts express CD40 to variable degrees, there is no information on CD40-dependent modulation of blast sensitivity to apoptotic signals. 9 Death receptor-mediated proapoptotic signals are transmitted via the so-called death-inducing signaling complex (DISC) formed upon oligomerization of CD95 by interaction with its ligand. 10 The oligomerized death domains (DDs) of the receptor associate with the cytoplasmic adapter molecule FADD with subsequent recruitment of procaspase-8 (FLICE) into the DISC. The apoptotic cascade is then initiated by autocatalytic cleavage of procaspase-8 and release of the active enzyme into the cytoplasm. The FLICE inhibitory protein (c-FLIP) can bind to the DISC and interfere with receptor-induced apoptosis. 11 c-FLIP occurs in 3 different isoforms as a result of alternative splicing: 2 short isoforms, c-FLIP Short (27 kDa) and c-FLIP Raji (26 kDa), and a long form c-FLIP Long (55 kDa). 12,13 While the short isoforms, thereafter called c-FLIP S and c-FLIP R , comprise only 2 death effector domains (DEDs) critical for interaction with the DISC, the long isoform contains an additional catalytically inactive C-terminal caspaselike domain. Depending on its expression level, c-FLIP L can serve as a dual regulator with both proapoptotic and antiapoptotic function. 14,15 Thus, it has been shown in adult T-cell leukemia that it is the equilibrium between FLIP and caspase-8 that regulates suscepti...
*The hematopoietic stem and progenitor cell (HSPC) compartment is subject to extensive quantitative genetic variation. We have previously shown that TGF-2 at low concentrations enhances flt3 ligand-induced growth of HSPCs, while it is potently antiproliferative at higher concentrations. This in vitro enhancing effect was subject to quantitative genetic variation, for which a quantitative trait locus (QTL) was tentatively mapped to chromosome 4 (chr.4). Tgfb2 ؉/؊ mice have a smaller and more slowly cycling HSPC compartment, which has a decreased serial repopulation capacity, and are less susceptible to the lethal effect of high doses of 5-fluorouracil. To unequivocally demonstrate that these phenotypes can be attributed to the enhancing effect of TGF-2 on HSPC proliferation observed in vitro and are therefore subject to mouse strain-dependent variation as well, we generated congenic mice where the telomeric region of chr.4 was introgressed from DBA/2 into C57BL/6 mice. In these mice, the enhancing effect of TGF-2 on flt3 signaling, but not the generic antiproliferative effect of high concentrations of TGF-2, was abrogated, confirming the location of this QTL, which we named tb2r1, on chr.4. These mice shared a smaller and more slowly cycling HSPC compartment and increased 5-fluorouracil resistance but not a decreased serial repopulation capacity with Tgfb2 ؉/؊ mice. The concordance of phenotypes between Tgfb2 ؉/؊ and congenic mice indicates that HSPC frequency and cycling are regulated by tb2r1, while an additional QTL in the telomeric region of chr.4 may regulate the serial repopulation capacity of hematopoietic stem cells.
CD40 and CD27, members of the tumor necrosis factor receptor (TNFR) family, are critical regulators of lymphocyte growth and differentiation. In B-cell precursor acute lymphoblastic leukemia (BCP-ALL), we prospectively assessed the impact of CD40 and CD27 on outcome in 121 children treated according to the CoALL06-97 protocol. Expression of both CD40 and CD27 was found to be significantly higher in low-than in high-risk patients as defined by standard clinical risk parameters such as age and white blood cell count. In addition, in multivariable analysis, a very high percentage of CD40 ؉ blasts at diagnosis was identified as an independent favorable prognostic factor for relapse-free survival. Of note, high CD40 expression particularly protected against late relapse. In B cells, CD40 is known to enhance both antigenpresenting capacity and sensitivity to proapoptotic signals. Yet, although CD40 ligation does result in significant upregulation of CD80/CD86 in our cohort, it is up-regulation of the death receptor CD95 that significantly correlates with the percentage of CD40 ؉ blasts. Thus very high expression of CD40 on BCP-ALL blasts is an independent prognostic marker indicative of superior relapse-free survival that may in part be due to CD40-dependent death receptor up-regulation. IntroductionAlthough the overall prognosis in B-cell precursor acute lymphoblastic leukemia (BCP-ALL) is good, identification of new prognostic factors may result in improved risk classification and treatment outcome. Long-term survival is critically influenced by blast sensitivity toward chemotherapeutic agents. Immunologic control mechanisms are also thought to play a role. [1][2][3] In normal B cells, homeostasis is maintained by an intricate regulatory network with the nerve growth factor/tumor necrosis factor (NGF/TNF) receptor/ ligand family of proteins playing a pivotal role in T cell/B cell interactions. [4][5][6][7][8] As adequate stimulation of effector cells as well as susceptibility of the target cells to apoptotic signals are required for optimal immunologic control, the capacity of B cells to respond to CD40 ligand (CD40L) stimulation is critical. In normal B cells, activation via the CD40 receptor promotes differentiation and results in increased expression of costimulatory molecules and the CD95 death receptor, another member of the TNF receptor (TNFR) family. 7,9-11 To various degrees, the CD40 receptor is also expressed on acute lymphoblastic leukemia (ALL) of the B-cell lineage. 12 In analogy to mature B cells, activation via CD40 turns leukemic blasts into efficient antigen-presenting cells mediated by up-regulation of MHC, adhesion, and costimulatory molecules. [13][14][15][16][17] In addition to promoting their antigenpresenting ability, in chronic lymphoblastic leukemia (CLL) it has been shown that CD40 ligation also induces CD95 expression, 18,19 although little is known about CD40-dependent CD95 modulation in BCP-ALL. CD27, another member of the TNF receptor family, also plays an important role in lymphoid di...
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