Vorinostat and Mithramycin A in combination therapy as an interesting strategy for the treatment of Sézary T lymphoma: a transcriptomic approach.

SAHA (vorinostat) is a histone deacetylase inhibitor approved by the USA Food and Drug Administration (FDA) for treating advanced refractory cutaneous T cell lymphomas. As SAHA alters the expression of many genes under control of the Sp1 transcription factor, we examined the effect of its association with the FDA-approved anticancer antibiotic Mithramycin A (MTR, plicamycin), a competitive inhibitor of Sp1 binding to DNA. Sézary syndrome (SS) cells, expanded ex vivo from peripheral blood mononuclear cells of 4 patients, were tested for their sensitivity to the drugs regarding cytotoxicity and differential responsive gene expression.

Natural killer cells in patients with polycythemia vera.

Natural killer cells (NK) are pivotal cells of innate immunity. They are potent antileukemic cytotoxic effectors. A defect in their cytotoxicity has been described in some hematopoietic malignancies such as acute myeloid leukemia, multiple myeloma and myelodysplastic syndromes.

Distribution of lymphocyte subpopulations in patients with polycythemia vera.

Polycythemia vera (PV) is a disease with slow development. Nonetheless, the immune response is unable to eliminate the uncontrolled proliferating hematopoietic cells, leading to treatment of patient by phlebotomy and/or cytotoxic drugs. In addition, a higher incidence of cancers is observed in PV patients, independently of treatment.

Effects of 5-azacytidine on natural killer cell activating receptor expression in patients with refractory anemia with excess of blasts.

Epigenetic drugs modify DNA methylation and are used in refractory anemia with excess of blasts (RAEB). These drugs may reactivate anti-oncogene expression and restore a normal phenotype instead of inducing antitumor toxicity, although they also have immunosuppressive effects on T-lymphocytes [1] In RAEB and acute myeloid leukemia, a defect in natural killer (NK) cell cytotoxicity has been shown, which relies on abnormal expression of activating receptors. Previous study has shown that 5-azacytidine impaired mRNA synthesis and induced apoptosis in NK cells [2].

Natural killer cells modulation in hematological malignancies.

Hematological malignancies (HM) treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed, due to remaining minimal residual disease. Therefore, sustainment of long-term remission is crucial, using either drug maintenance treatment or by boosting or prolonging an immune response. Immune system has a key role in tumor surveillance.

Expression of activating receptors on natural killer cells from AIDS-related lymphoma patients.

Background: Abnormal NK phenotype and cytotoxic functions have been described in acute myeloid leukemia, chronic lymphocytic leukemia, myeloma and myelodysplastic syndromes. Defective NK cytotoxicity is due to decreased expression of the Natural Cytotoxicity Receptors (NCRs), 2B4/CD244/p38, or NKG2D. This prompted us to test the expression of these molecules on circulating NK cells from patients with AIDS-related lymphomas (RL) in comparison with HIV + patients without lymphoma, healthy subjects and HIV-negative patients with lymphoma.

Differential expression of natural killer cell activating receptors in blood versus bone marrow in patients with monoclonal gammopathy.

In monoclonal gammopathies (MG) and multiple myeloma (MM), normal natural cytotoxicity receptors (NCR) expression (NCR1/NKp46, NCR2/NKp44, NCR3/NKp30) is observed in natural killer (NK) cells. Nonetheless, except in plasma cell leukemia, few tumor plasmocytes are present in PB, while NK studies have been performed on peripheral blood (PB). For this reason we focused our attention on NK from bone marrow (BM).

Hematological malignancies escape from NK cell innate immune surveillance: mechanisms and therapeutic implications.

Hematological malignancies treatment improved over the last years resulting in increased achievement of complete or partial remission, but unfortunately high relapse rates are still observed. Therefore, sustainment of long-term remission is crucial. Immune system has a key role in tumor surveillance.

Expression of natural killer cell activating receptors in patients with chronic lymphocytic leukaemia.

Recent advances in chronic lymphocytic leukaemia (CLL) treatment, more particularly through upfront use of anti-CD20 monoclonal antibodies, have prolonged patient progression-free survival. Nonetheless, apart from allogeneic stem cell transplantation, no curative treatment is available. One possible explanation for the lack of cure in CLL could be a defective immune anti-tumour response.

A role for HVEM, but not lymphotoxin-beta receptor, in LIGHT-induced tumor cell death and chemokine production.

The TNF member LIGHT also known as TL4 or TNFSF14) can play a major role in cancer control via its two receptors; it induces tumor cell death through lymphotoxin-beta receptor (LT-betaR) and ligation to the herpes virus entry mediator (HVEM) amplifies the immune response. By studying the effect of LIGHT in the transcriptional profile of a lymphoid malignancy, we found that HVEM, but not LT-betaR, stimulation induces a significant increase in the expression of chemokine genes such as IL-8, and an unexpected upregulation of apoptotic genes. This had functional consequences, since LIGHT, or HVEM mAb, thus far known to costimulate T- and B-cell activation, induced chronic lymphocytic leukemia cell death.

Reversing the multidrug resistance in acute leukemia: until the leukemia initiating cell?

Reversal of drug resistance is of pivotal importance in order to improve the results of chemotherapy. Monitoring of such reversal is necessary in order to analyze the results of clinical trials. Nonetheless, the leukemia cell population to eradicate is the leukemia initiating cells characterized by a CD34+CD38- phenotype.

How to restore normal innate antitumor immunity in acute leukemia?

Restoration of immune functions is of importance in tumour eradication, more particularly regarding the residual disease. The challenge is probably to restore both innate and specific immune response, both required to overcome the various tumour escape mechanisms developed by leukemia cells. In the work of Lion et al.

Rank ligand stimulation induces a partial but functional maturation of human monocyte-derived dendritic cells.

Mature dendritic cells (DC) are efficient, antigen-presenting cells required for the stimulation of naive T lymphocytes. Many members of the tumour necrosis factor (TNF) receptor family are involved in DC maturation, such as Fas, CD40, OX40L, LIGHT (homologous to lymphotoxins, exhibits inducible expression, and competes with HSV glycoprotein D for herpes virus entry mediator (HVEM), a receptor expressed by T lymphocytes) or RANK (receptor activator of NFkappaB), with different, but often overlapping effects. We focused our attention on RANK DC stimulation, since RANK ligand (RL) is expressed on activated T lymphocytes with different kinetic and expression patterns from the other members of TNF family previously cited.

Deficient expression of NCR in NK cells from acute myeloid leukemia: Evolution during leukemia treatment and impact of leukemia cells in NCRdull phenotype induction.

Natural killer (NK) cells play an important role in tumor-cell clearance, particularly against leukemia, as shown by killer cell inhibitory receptor (KIR)-mismatched allogeneic stem cell transplantation. Analysis of in vitro IL-2-expanded NK cells from patients with myelocytic/monocytic acute myeloid leukemia (AML-NK cells) has revealed poor cytolytic functions because of deficient expression of pivotal activation molecules-the natural cytotoxicity receptors (NCRs) NKp30, NKp44, and NKp46. To exclude the possibility that this observation was caused by the in vitro amplification of a small NCR(dull) population, we analyzed the AML-NK phenotype directly, without any in vitro expansion.

The co-expression of 2B4 (CD244) and CD160 delineates a subpopulation of human CD8+ T cells with a potent CD160-mediated cytolytic effector function.

Within human CD8+ T lymphocytes, the CD27-CD45RAhigh or CD56+ phenotypes contribute to precisely define the cells with CTL effector function. Novel markers were demonstrated to correlate with CTL properties, such as the 2B4 (CD244) receptor, a member of the CD2 subset of the immunoglobulin superfamily or the glycosylphosphatidylinositol-anchored CD160 receptor. We performed a study of these markers to further define the population of effectors with CTL functions.

[New insights into cytotoxic effector cells].

Cytotoxic immune cells play a role against infectious or tumour invasion. There are two types of cytotoxic cells : those involved in innate or natural immunity (natural killer cells, Tgammadelta lymphocytes, NKT cells) and those involved in the adaptive or acquired immunity (cytotoxic T lymphocytes). Recent advances in immunology have allowed the characterisation of unconventional cytotoxic populations, to better individualise the real cytotoxic cells within the traditional CD8+ T-cell population, and finally to get more insights into the activation of the cytotoxicity properties, in particular with regard to NK cells.

Non-Hodgkin's lymphoma after kidney transplantation: a single institution study.

We treated at our institution six patients with kidney transplantation and lymphoma. After the end of chemotherapy, re-introduction of therapeutic immune suppression was not necessary since, with a significant follow-up (median follow-up of 26 months, range 12-36), no patient had severe renal function deterioration. These preliminary data suggest that, after lymphoma treatment, immune suppression can be withhold at least for 2 years.

Defective killing of dendritic cells by autologous natural killer cells from acute myeloid leukemia patients.

At the frontier between innate and adaptive immunity, dendritic cells (DCs) secrete numerous cytokines and express costimulatory molecules that initiate or enhance natural killer (NK) and T-lymphocyte responses. NK cells also regulate DC physiology by killing immature DCs (iDCs), thus limiting inflammation and inappropriate T-lymphocyte tolerization. In a previous study, we have reported that NK cells from acute myeloid leukemia patients (AML-NK cells) have deficient natural cytotoxicity receptor (NCR) expression.

LIGHT costimulates CD40 triggering and induces immunoglobulin secretion; a novel key partner in T cell-dependent B cell terminal differentiation.

The T cell-dependent differentiation and function of B lymphocytes are tightly regulated by TNF ligands (L) and receptors interactions, such as CD40/CD40L, CD27/CD70 and CD134/CD314L. The LIGHT/HVEM system [homologous to lymphotoxin, inducible expression, competing for GpD of herpes virus, that binds to the herpes virus entry mediator (HVEM), and is expressed on activated T lymphocytes) focused our attention since HVEM has a large distribution that, in addition to T cells, DC or NK, includes tumor and normal B lymphocytes. HVEM was expressed on memory and naive B cells from peripheral blood or tonsils, but not on germinal center (GC) B cells.

Natural killer cells and immunity against cancer.

Extract: Under specific conditions, the immune response can eradicate tumors. The specific response against cancer requires the recognition of target molecules (antigens) by a subpopulation of white blood cells, the T lymphocytes. These antigens are exclusively or predominantly expressed by the tumor cells.

NK cells: innate immunity against hematological malignancies?

Recent advances in the treatment of malignant haemopathies enable increased remission and cure rates, however, many patients relapse and finally die. Although specific immunity mediated by cytolytic T-lymphocytes might have an anti-cancer role, tumours escape from T-cell-based immune surveillance using various mechanisms, such as downregulation, mutation or loss of HLA class I molecules. As a consequence, these transformed cells could become targets for natural killer (NK) cells, whose cytotoxic capabilities are not blocked by HLA class I molecule engagement by specific inhibitory receptors.

Intensive sequential chemotherapy with hematopoietic growth factor support for non-Hodgkin lymphoma in patients infected with the human immunodeficiency virus.

Background: Optimal treatment of human immunodeficiency virus (HIV)-associated non-Hodgkin lymphoma (NHL) has yet to be defined, because chemotherapy could exacerbate immunodeficiency, with subsequent adverse effects for patients.

Methods: The authors investigated the feasibility of an intensive chemotherapy regimen for HIV-associated NHL. Thirty-eight patients were treated with a first course of cyclophosphamide (Cy), vincristine, and prednisone; followed by 3 courses of high-dose Cy (2000 mg/m2), doxorubicin (Doxo; 50 mg/m2), vincristine, and prednisone (modified high-dose CHOP); 1 course of high-dose methotrexate (MTX; 8000 mg/m2); and 1 course of high-dose cytarabine (8000 mg/m2).

Immunobiology of haematological malignant disorders: the basis for novel immunotherapy protocols.

The immune system is a complex arrangement of cellular interactions that preserve the integrity of a organism by elimination of all elements judged dangerous. However, the development of tumours in immunocompetent patients suggests the existence of an imbalance that favours tumour cells against the immune response. What are the different possibilities for reversing this process to drive an efficient antitumour response? We discuss, focusing on the haematological features, classic immunity (ie, antigen-specific and HLA-restricted immunity).