Autoreactive, Cytotoxic T Lymphocytes Specific for Peptides Derived from Normal B-Cell Differentiation Antigens in Healthy Individuals and Patients with B-Cell Malignancies

Grube, Matthias; Rezvani, Katayoun; Wiestner, Adrian; Fujiwara, Hiroshi; Sconocchia, Giuseppe; Melenhorst, J. Joseph; Hensel, Nancy F.; Marti, Gerald E.; Kwak, Larry W.; Wilson, Wyndham; Barrett, John

doi:10.1158/1078-0432.ccr-03-0075

Cited by 19 publications

(19 citation statements)

References 64 publications

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“…Affinity-autoreactive cytotoxic T lymphocytes (CTLs) have already been described, especially against peptide CD19 or CD20 antigens. 52 These different strategies could apply to the ⌬CD20 protein. Based on our preliminary data for vaccination, in a transgenic murine model expressing human HLA, we have demonstrated that the splice junction area of the protein could be targeted to direct a specific CTL response, and that autoreactive CTLs against ⌬CD20 peptide junctions exist in healthy people.…”

Section: Discussionmentioning

confidence: 99%

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Henry

Deschamps

Rohrlich

et al. 2010

Blood

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Human CD20 is a B-cell lineage-specific marker expressed by normal and leukemic B cells from the pre-B to the plasmacell stages and is a target for rituximab (RTX) immunotherapy. A CD20 reverse transcriptase-polymerase chain reaction (PCR) on B-cell lines cDNA yielded a short PCR product (⌬CD20) corresponding to a spliced mRNA transcript linking the exon 3 and exon 7 ends. We established here that this novel, alternatively spliced CD20 transcript is expressed and detectable at various levels in leukemic B cells, lymphoma B cells, in vivo tonsil-or in vitro CD40L-activated B cells, and Epstein-Barr virus (EBV)-transformed B cells, but not in resting CD19 ؉ -or CD20 ؉ -sorted B cells from peripheral blood or bone marrow of healthy donors. The truncated CD20 sequence is within the reading frame, codes a protein of 130 amino acids (ϳ 15-17 kDa) lacking large parts of the 4 transmembrane segments, suggesting that ⌬CD20 is a nonanchored membrane protein. We demonstrated the translation into a ⌬CD20 protein which is associated with the membrane CD20 protein and showed its involvement in RTX resistance. Study of patient samples before and after RTX resistance or escape confirms our in vitro findings. (Blood. 2010;115:2420-2429) Introduction CD20 (MS4A1) is a 33-to 37-kDa nonglycosylated transmembrane (TM) phosphoprotein that is widely expressed throughout B-lymphocyte ontogeny, in normal or malignant B cells. 1 The 16-kb gene encoding human CD20, consisting of 8 exons, has been mapped to chromosome 11 (11q12-q13) and belongs to the MS4A (membrane spanning 4A) gene family localized within a cluster of related genes (MS4A1 to MS4A11). 2 Its transcription leads to 3 mRNA isoforms: a dominant 2.8-kb transcript, using exons 1 to 8; a second exon 1-spliced transcript shorter by 263 bp; and a third, minor 3.4-kb transcript, 3 all encoding a full-length CD20 protein.The CD20 protein consists of cytoplasmic N-and C-termini and 4 hydrophobic regions for anchoring the molecule in the membrane. 4 A total of 3 isoforms have been identified, including a predominant 33-kDa molecule and 2 isoforms of 34.5 and 36 kDa, resulting from differential phosphorylation states (on serine and threonine residues) in relation to B-cell stimulation and proliferation. 5 CD20 appears to play a role in Ca ϩϩ conductance 6 and is also involved in cell-cycle progression by interaction with src family kinases. 7 Finally, CD20 circulating form has been identified in chronic lymphocytic leukemia (CLL), Hodgkin disease, or nonHodgkin lymphoma (NHL), and in healthy persons. 8 CD20 expression at the cell surface of malignant B cells makes it a target for monoclonal antibody (mAb) therapy. Rituximab (RTX), the first US Food and Drug Administration (FDA)-approved mAb for clinical therapy, targets the CD20 antigen 9 and leads to CD20-expressing B-cell depletion through different mechanisms 9,10 (for review, see Cartron et al 11 ). Thus, RTX is widely used against B-cell malignancies and also for autoimmune diseases such as rheumatoid arthritis, 12 steroid refract...

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Section: Discussionmentioning

confidence: 99%

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Henry

Deschamps

Rohrlich

et al. 2010

Blood

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“…CD40-B cells were generated as previously described (25). In brief, irradiated (75 Gy) human CD40L-transfected murine fibroblasts (LTK-CD40L), kindly provided by Dr. Van Kooten (Department of Nephrology, Leiden University Medical Centre, Leiden, Netherlands), were plated in six-well plates (BD Bioscience, Franklin Lakes, NJ) at a concentration of 0.1 × 10 6 cells/well, in RPMI complete medium [25 mmol/L HEPES buffer (pH 7.55), 2 mmol/L Lglutamine, 100 units/mL penicillin, and 100 μ/mL streptomycin; Life Technologies, Inc., Gaithersburg, MD] supplemented with 10% FCS and cultured overnight at 37°C, 5% CO 2 .…”

Section: Generation Of B-cell Linesmentioning

confidence: 99%

In vitro Induction of Myeloid Leukemia–Specific CD4 and CD8 T Cells by CD40 Ligand – Activated B Cells Gene Modified to Express Primary Granule Proteins

Fujiwara

Melenhorst

Ouriaghli

et al. 2005

Clinical Cancer Research

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The primary granule proteins (PGP) of myeloid cells are a source of multiple antigens with immunotherapeutic potential for myeloid leukemias. Therefore, we developed a method to induce T-cell responses to PGP protein sequences. We found that gene-transfected antigen-presenting cells efficiently expand functionally competent PGP-specific CD4 and CD8 T cells. The system was optimized using T-cell responses to autologous CD40-activated B cells (CD40-B) transfected with a cytomegalovirus pp65-encoding expression vector. To generate leukemia-specific T cells, expression vectors encoding the PGP proteinase 3 (PR3) human neutrophil elastase, and cathepsin-G were transfected into CD40-B cells to stimulate postallogeneic stem cell transplantation T cells from five patients with myeloid and three with lymphoid leukemias. T-cell responses to PGP proteinase 3 and human neutrophil elastase were observed in CD8 + and CD4 + T cells only in patients with myeloid leukemias. T-cell responses against cathepsin-G occurred in both myeloid and lymphoblastic leukemias. T cells from a patient with chronic myelogenous leukemia (CML) and from a posttransplant CML patient, expanded against PGP, produced IFN-γ or were cytotoxic to the patient's CML cells, demonstrating specific antileukemic efficacy. This study emphasizes the clinical potential of PGP for expansion and adoptive transfer of polyclonal leukemia antigen-specific T cells to treat leukemia.Primary granule proteins (PGP) are aberrantly expressed in CD34-positive cells in myeloid leukemias. This abnormal expression may contribute to the leukemic phenotype. One of these proteins, human neutrophil elastase (HNE), may be responsible for the clonal dominance of chronic myeloid leukemia (CML) cells (1,2). Due to their aberrant and high expression in myeloid leukemic progenitor cells, PGP are of great interest as a source of leukemia-restricted antigens for immunotherapy. Proteinase 3 (PR3), HNE, and peptides derived from PR3 (PR1, PR7) can induce T cells cytotoxic to myeloid leukemia progenitors but not normal cells (3)(4)(5). Furthermore, PR3-and HNE-specific CD4 and CD8 T cells can be generated from healthy donors, facilitating adoptive immunotherapy following allogeneic stem cell transplantation (6-8). PR1, an HLA-A2-binding epitope originally identified in PR3, was also found in HNE, and we previously found that HNE-pulsed antigen-presenting cells (APC) allowed the generation of PR1-specific CD8 T cells recognizing CML progenitor cells (8) one antigenic epitope has arisen from two closely related proteins. Cathepsin-G, another PGP, can also be processed and presented by CML progenitor cells (9). These data suggest that PGP can serve as important immunotherapeutic target antigens for myeloid leukemias.Given the therapeutic potential of PGP-specific cytotoxic T lymphocytes, an important issue is how best to develop clinically applicable immunotherapeutic strategies with these proteins. Most translational research has focused on using small peptide sequences with defined bind...

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“…Studies suggest that CD8+ T cells may directly target lymphoma cells[31]. Higher stromal density of CD8+ T cells significantly predicted improved patient survival in our cohort of HIV-related DLBCL, independent of the IPI score.…”

Section: Discussionmentioning

confidence: 57%

Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival

Chao

Silverberg

et al. 2015

Aids

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Objective Understanding tumor microenvironment and its impact on prognosis of HIV-related lymphomas may provide insight into novel therapeutic strategies. Design We characterized the relationship between infiltrating immune cells with tumor characteristics, HIV disease history and survival in 80 HIV-related diffuse large B-cell lymphoma (DLBCL) patients diagnosed in the era of combined antiretroviral therapy (1996–2007) at Kaiser Permanente (KP) California. Eighty HIV-unrelated DLBCL patients were included for comparison. Methods Data on patients’ clinical history were obtained from KP’s electronic health records. The density of stromal CD4+, CD8+ and FOXP3+ T cells and CD68+ macrophages, as well as tumor molecular characteristics were examined using immunohistochemistry. The associations between stromal immune infiltration and patient’s clinical history or tumor characteristics were examined using Kruskal Wallis tests or Peasrons’ correlation coefficient. The effect of stromal immune infiltration on two-year mortality was evaluated in multivariable logistic regression. Results Compared to HIV-unrelated DLBCL, patients with HIV-related DLBCL had significantly reduced stromal CD4+ and FOXP3+ T cells, but increased density of macrophages. Increased density of stromal macrophages was correlated with lower circulating CD4 cell count at DLBCL diagnosis. Tumor molecular characteristics, including BCL6, p53 and cMYC expression, but not EBV infection status, were significantly correlated with stromal immune infiltration, particularly FOXP3+ T cells. A higher density of infiltrating CD8+ T cell was significantly associated with reduced mortality in HIV-related DLBCL patients [odds ratio=0.30 (0.09–0.97) for ≥25% vs. <10%]. Conclusion These data provide evidence for the prognostic significance of cytotoxic T cells in determining outcomes of HIV-related lymphoma.

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Autoreactive, Cytotoxic T Lymphocytes Specific for Peptides Derived from Normal B-Cell Differentiation Antigens in Healthy Individuals and Patients with B-Cell Malignancies

Cited by 19 publications

References 64 publications

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

Identification of an alternative CD20 transcript variant in B-cell malignancies coding for a novel protein associated to rituximab resistance

In vitro Induction of Myeloid Leukemia–Specific CD4 and CD8 T Cells by CD40 Ligand – Activated B Cells Gene Modified to Express Primary Granule Proteins

Stromal immune infiltration in HIV-related diffuse large B-cell lymphoma is associated with HIV disease history and patient survival

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