Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy

Hoogendoorn, Mels; Wolbers, Judith Olde; Smit, Willem A.; Schaafsma, Martyn Ronald; Barge, Renée M. Y.; Willemze, R.; Falkenburg, J.H. Frederik

doi:10.1038/sj.leu.2403358

Cited by 28 publications

(21 citation statements)

References 41 publications

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“…It is possible that the Th1 cell-CLL cell partnership is consolidated by macrophages. In this regard, it is relevant that CLL cells can secrete proinflammatory type 1 cytokines, such as IL-12 (35) and TNF-a, and express TNF-a receptors (14). Moreover, CLL cells secrete IL-1a, IL-1b (36), and IFN-g (37).…”

Section: Discussionmentioning

confidence: 99%

Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell–Derived IFN-γ by a T-bet–Dependent Mechanism

Bürgler

Gimeno

Parente-Ribes

et al. 2015

The Journal of Immunology

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Chronic lymphocytic leukemia (CLL) is a B cell malignancy associated with increased levels of inflammatory cytokines. Similarly, expression of CD38 on CLL cells correlates with CLL cell survival and proliferation, but the mechanisms that regulate CD38 expression and inflammatory cytokines remain unclear. We have recently demonstrated that patients have CLL-specific Th cells that support CLL proliferation. In this article, we show that CLL cells attract such Th cells, thereby establishing an Ag-dependent collaboration. Blocking experiments performed in vitro as wells as in vivo, using a xenograft model, revealed that secretion of IFN-γ was a major mechanism by which CLL-specific Th cells increased CD38 on CLL cells. The expression of the transcription factor T-bet in peripheral blood CLL cells significantly correlated with CD38 expression, and transient transfection of CLL cells with T-bet resulted in T-bethiCD38hi cells. Finally, chromatin immunoprecipitation experiments revealed that T-bet can bind to regulatory regions of the CD38 gene. These data suggest that CLL cells attract CLL-specific Th cells and initiate a positive feedback loop with upregulation of T-bet, CD38, and type 1 chemokines allowing further recruitment of Th cells and increased type 1 cytokine secretion. This insight provides a cellular and molecular mechanism that links the inflammatory signature observed in CLL pathogenesis with CD38 expression and aggressive disease and suggests that targeting the IFN-γ/IFN-γR/JAK/STAT/T-bet/CD38 pathway could play a role in the therapy of CLL.

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Section: Discussionmentioning

confidence: 99%

Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell–Derived IFN-γ by a T-bet–Dependent Mechanism

Bürgler

Gimeno

Parente-Ribes

et al. 2015

The Journal of Immunology

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“…This is supported by our study demonstrating that leukemic cells can acquire a professional APC phenotype in vivo upon interaction and release of proinflammatory cytokines by allo-reactive CD41 T cells. 46 Moreover, we previously demonstrated that not only AML blasts, 47,48 but also other leukemic cells, [46][47][48][49][50] upregulated expression of HLA, adhesion, and costimulatory molecules in the presence of soluble factors and acquired an enhanced capacity to stimulate allogeneic T cells in vitro.…”

Section: Discussionmentioning

confidence: 99%

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Stevanović

Bergen

Luxemburg-Heijs

et al. 2013

Blood

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Key Points• GVHD after HLA-DPB1-mismatched CD41 DLI after TCD-alloSCT is mediated by allo-reactive HLA-DPB1-directed CD41 T cells.• Viral infections after TCDalloSCT can induce HLA class II on nonhematopoietic tissues, making them targets for CD41 T cells in GVHD.CD81 T cell-depleted (TCD) donor lymphocyte infusion (DLI) after TCD allogeneic hematopoietic stem cell transplantation (alloSCT) has been associated with a reduced risk of graft-versus-host disease (GVHD) while preserving conversion to donor hematopoiesis and antitumor immunity, providing a rationale for exploring CD41 T cell-based immunotherapy for hematologic malignancies. Here, we analyzed the clinical course and specificity of T cell immune responses in 2 patients with acute myeloid leukemia (AML) who converted to full-donor chimerism but developed severe acute GVHD after prophylactic CD41 DLI after 10/10-HLA-matched, but HLA-DPB1-mismatched TCD-alloSCT. Clonal analysis of activated T cells isolated during GVHD demonstrated allo-reactivity exerted by CD41 T cells directed against patient-mismatched HLA-DPB1 molecules on hematopoietic cells and skin-derived fibroblasts only when cultured under inflammatory conditions. At the time of CD41 DLI, both patients contained residual patient-derived T cells, including cytomegalovirus (CMV)-specific T cells as a result of CMV reactivations.Once activated by CMV antigens, these CMV-specific T cells could stimulate HLA-DPB1-specific CD41 T cells, which in turn could target nonhematopoietic tissues in GVHD. In conclusion, our data demonstrate that GVHD after HLA-DPB1-mismatched CD41 DLI can be mediated by allo-reactive HLA-DPB1-directed CD41 T cells and that ongoing viral infections inducing HLA class II expression on nonhematopoietic cells may increase the likelihood of GVHD development. This trial is registered at http://www.controlled-trials.com/ISRCTN51398568/LUMC as #51398568. (Blood. 2013;122(11):1963-1973 IntroductionIn allogeneic hematopoietic stem cell transplantation (alloSCT), T-cell depletion of the graft efficiently prevents the occurrence of severe acute graft-versus-host disease [GVHD]) 1,2 but also adversely affects posttransplant antitumor and antipathogen immunity.1-3 Early intervention with donor lymphocyte infusion (DLI) after T cell-depleted (TCD)-alloSCT may prevent relapse of the malignancy and improve immune reconstitution against pathogens but is frequently associated with reintroduction of GVHD. 4,5 Therefore, exploration of treatment strategies to improve the balance between graft-versus-leukemia (GVL) reactivity and antipathogen immunity and GVHD is warranted.To minimize the risk of GVHD, patients are preferably transplanted with stem cell grafts from HLA-matched sibling or unrelated donors (URD).6 HLA matching is generally performed for HLA-A, -B, -C, -DRB1, and -DQB1 alleles (10/10 match) but not for HLA-DPB1. Therefore, 70% to 80% of URD alloSCT are HLA-DPB1-mismatched. 6,7 In contrast to HLA class I, constitutive expression of HLA class II molecules is mainly confined to normal...

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“…It is known that antigen-presenting cells (APC) are required for efficient induction of anti-tumor immunity in vivo, and that APC acquire a mature phenotype on interaction with T-helper cells. [8][9][10]19 In vitro, in the presence of a variety of soluble factors, various types of leukemic cells, including CML, 20,21 acute myeloid leukemia, [21][22][23] ALL 21,22 and chronic lymphocytic leukemia, 21,24 cells have been shown to differentiate into leukemic-APC displaying increased expression of HLA-class II, adhesion and costimulatory molecules and an enhanced capacity to stimulate allogeneic T cell responses. [20][21][22][23][24] On the basis of these findings, it can be speculated that the efficacy of DLI depends on the capacity of leukemic cells to become leukemic-APC in vivo.…”

Section: Introductionmentioning

confidence: 99%

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

et al. 2011

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Adoptive immunotherapy with donor lymphocyte infusion (DLI) after allogeneic stem cell transplantation (alloSCT) may not only mediate Graft-versus-Leukemia (GvL) reactivity, but also induce Graft-versus-Host Disease (GvHD). As HLA-class II molecules are predominantly expressed on hematopoietic cells, CD4 þ T cells may selectively mediate GvL reactivity without GvHD. Here, we assessed the capacity of human CD4 þ T cells to act as sole mediators of GvL reactivity in a NOD/scid mouse model for human acute lymphoblastic leukemia and chronic myeloid leukemia in lymphoid blast crisis. Highly purified CD4 þ DLI eradicated the leukemic cells. The anti-tumor immunity was mediated by a polyclonal CD4 þ T cell response comprising cytokine-producing T-helper and cytolytic T-effector cells directed against the mismatched HLA-class II molecules of the patients. Furthermore, primary leukemic cells acquired an antigen-presenting cell (APC) phenotype in vivo after DLI, as well as in vitro after co-culture with leukemia-specific CD4 þ T cells. In conclusion, our results show that CD4 þ T cells can be strong mediators of anti-tumor immunity, and provide evidence that cross-talk between CD4 þ T cells and leukemic cells is the basis for induction of leukemic cells with an APC phenotype. These data emphasize the clinical relevance of CD4 þ T cell based immunotherapy as treatment modality for hematological malignancies after alloSCT.

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Generation of B-cell chronic lymphocytic leukemia (B-CLL)-reactive T-cell lines and clones from HLA class I-matched donors using modified B-CLL cells as stimulators: implications for adoptive immunotherapy

Cited by 28 publications

References 41 publications

Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell–Derived IFN-γ by a T-bet–Dependent Mechanism

Chronic Lymphocytic Leukemia Cells Express CD38 in Response to Th1 Cell–Derived IFN-γ by a T-bet–Dependent Mechanism

HLA class II upregulation during viral infection leads to HLA-DP–directed graft-versus-host disease after CD4+ donor lymphocyte infusion

Human allo-reactive CD4+ T cells as strong mediators of anti-tumor immunity in NOD/scid mice engrafted with human acute lymphoblastic leukemia

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