CLL, Immunology

The Src family kinases (SFKs) Lck and Lyn are crucial for lymphocyte development and function. Albeit tissue-restricted expression patterns the two kinases share common functions; the most pronounced one being the phosphorylation of ITAM motifs in the cytoplasmic tails of antigenic receptors. Lck is predominantly expressed in T lymphocytes; however, it can be ectopically found in B-1 cell subsets and numerous pathologies including acute and chronic B-cell leukemias. The exact impact of Lck on the B-cell signaling apparatus remains enigmatic and is followed by the long-lasting question of mechanisms granting selectivity among SFK members...

Large granular lymphocytic (LGL) leukemia is a chronic lymphoproliferative disease of cytotoxic T cells or NK cells with LGL morphology and frequently complicated cytopenia and/or different autoimmune diseases, which often require medical interventions, although LGL leukemia itself is seldom lethal. Immunologic dysregulations in LGL leukemia contribute to the development of complications, for example, neutropenia with the involvement of Fas ligand system and, in pure red cell aplasia, which is a common complication among the patients of East Asian origin, impairing erythroid developments by cytotoxic T cells...

BACKGROUND: The pathogenesis of eosinophilic dermatosis of hematologic malignancy (EDHM) is poorly understood. Previously thought to be a hypersensitivity reaction to insect bites, immune dysregulation and cytokine imbalance are now thought to be responsible. Its prognostic significance is unclear. OBJECTIVE: To describe the clinical, pathological and immunological findings in a series of oncohematological patients with EDHM. METHODS: An observational prospective cohort study of oncohematological patients receiving a diagnosis of EDHM between April 2017 and December 2018...

Chronic Lymphocytic Leukemia (CLL) co-evolves with its own microenvironment where inflammatory stimuli including Toll Like Receptors (TLR) signaling can protect CLL cells from spontaneous and drug induced apoptosis by upregulating IκBζ, an atypical co-transcription factor. To dissect IκBζ-centered signaling pathways, we performed a gene expression profile of primary leukemic cells expressing either high or low levels of IκBζ after stimulation, highlighting that IκBζ is not only an inflammatory gene but it may control metabolic rewiring of malignant cells thus pointing to a novel potential opportunity for therapy...

Adoptive T-cell transfer (ACT) therapies, including of tumor infiltrating lymphocytes (TILs) and T cells gene-modified to express either a T cell receptor (TCR) or a chimeric antigen receptor (CAR), have demonstrated clinical efficacy for a proportion of patients and cancer-types. The field of ACT has been driven forward by the clinical success of CD19-CAR therapy against various advanced B-cell malignancies, including curative responses for some leukemia patients. However, relapse remains problematic, in particular for lymphoma...

Recent studies have demonstrated that a particular group of nucleated cells that exhibit erythroid markers (TER119 in mice and CD235a in humans) possess the ability to suppress the immune system and promote tumor growth. These cells are known as CD45+ erythroid progenitor cells (EPCs). According to our study, it appears that a subset of these CD45+ EPCs originate from B lymphocytes. Under conditions of hypoxia, mouse B lymphoma cells are capable of converting to erythroblast-like cells, which display phenotypes of CD45+ TER119+ cells, including immunosuppressive effects on CD8 T cells...

T cell dysregulation and shift to T helper 2 responses, boosting tumor microenvironment support, contributes to the survival of leukemic B cells in Chronic Lymphocytic Leukemia. Interleukin (IL)-25 is involved in the initiation of T helper 2 cell responses. Signal transduction of IL-25 begins with the heterodimer receptor (IL-17RA/IL-17RB). The presence of IL-25 in the tumor microenvironment may affect the supportive effects of T cells in the surrounding tumor cell environment. The purpose of this study was to evaluate the role of IL-25 in the biology of CLL...

Subset #201 is a clinically indolent subgroup of patients with chronic lymphocytic leukemia defined by the expression of stereotyped, mutated IGHV4-34/IGLV1-44 BCR Ig. Subset #201 is characterized by recurrent somatic hypermutations (SHMs) that frequently lead to the creation and/or disruption of N-glycosylation sites within the Ig H and L chain variable domains. To understand the relevance of this observation, using next-generation sequencing, we studied how SHM shapes the subclonal architecture of the BCR Ig repertoire in subset #201, particularly focusing on changes in N-glycosylation sites...

BACKGROUND: It is well established that inflammation and platelets promote multiple processes of cancer malignancy. Recently, platelets have received attention for their role in carcinogenesis through the production of microvesicles or platelet-derived microparticles (PMPs), which transfer their biological content to cancer cells. We have previously characterized a new subpopulation of these microparticles (termed mito-microparticles), which package functional mitochondria. The potential of mitochondria transfer to cancer cells is particularly impactful as many aspects of mitochondrial biology (i...

Chronic lymphocytic leukemia (CLL) is a malignant blood disorder in which there is an excess of white blood cells (lymphocytes) in blood and lymphoid tissues. CLL patients experience different clinical behaviors with diversity in disease course and outcome. Accordingly, prognostic markers are crucial for employing appropriate therapy protocols. CD163 (cluster of differentiation 163) is a monocyte/macrophage receptor. Soluble CD163 (sCD163) is an emerging prognostic player in the field of hematopoietic neoplasms...

The Bruton's tyrosine kinase (BTK) inhibitor ibrutinib is widely used for treatment of patients with relapsed/refractory or treatment-naïve Chronic Lymphocytic Leukemia (CLL). A prominent effect of ibrutinib is to disrupt the retention of CLL cells from supportive lymphoid tissues, by altering BTK-dependent adhesion and migration. To further explore the mechanism of action of ibrutinib and its potential impact on non-leukemic cells, we quantified multiple motility and adhesion parameters of human primary CLL cells and non-leukemic lymphoid cells...

Monocyte-derived macrophages help maintain tissue homeostasis and defend the organism against pathogens. In tumors, recent studies have uncovered complex macrophage populations, including tumor-associated macrophages, which support tumorigenesis through cancer hallmarks such as immunosuppression, angiogenesis, or matrix remodeling. In the case of chronic lymphocytic leukemia, these macrophages are known as nurse-like cells (NLCs) and they protect leukemic cells from spontaneous apoptosis, contributing to their chemoresistance...

Forkhead box (FOX) class O (FOXO) proteins are a dynamic family of transcription factors composed of four family members: FOXO1, FOXO3, FOXO4 and FOXO6. As context-dependent transcriptional activators and repressors, the FOXO family regulates diverse cellular processes including cell cycle arrest, apoptosis, metabolism, longevity and cell fate determination. A central pathway responsible for negative regulation of FOXO activity is the phosphatidylinositol-3-kinase (PI3K)-AKT signalling pathway, enabling cell survival and proliferation...

Cancer is a disease with ecological and evolutionary unity, which seriously affects the survival and quality of human beings. Currently, many reports have suggested Gas6 plays an important role in cancer. Binding of gas6 to TAM receptors is associated with the carcinogenetic mechanisms of multiple malignancies, such as in breast cancer, chronic lymphocytic leukemia, non-small cell lung cancer, melanoma, prostate cancer, etc., and shortened overall survival. It is accepted that the Gas6/TAM pathway can promote the malignant transformation of various types of cancer cells...

The signaling lymphocytic activation molecule (SLAM) family receptors were discovered in immune cells for the first time. The SLAM-family receptors are a significant player in cytotoxicity, humoral immune responses, autoimmune diseases, lymphocyte development, cell survival, and cell adhesion. There is growing evidence that SLAM-family receptors have been involved in cancer progression and heralded as a novel immune checkpoint on T cells. Previous studies have reported the role of SLAMs in tumor immunity in various cancers, including chronic lymphocytic leukemia, lymphoma, multiple myeloma, acute myeloid leukemia, hepatocellular carcinoma, head and neck squamous cell carcinoma, pancreas, lung, and melanoma...

Phosphoinositide 3-kinase delta (PI3Kδ) plays key roles in normal B cell activation and is chronically activated in malignant B cells. Targeting of PI3Kδ using FDA-approved drugs Idelalisib or Umbralisib has shown efficacy in treatment of multiple B cell malignancies. Duvelisib, an inhibitor targeting both PI3Kδ and PI3Kγ (PI3Kδγi) has also been used for treatment of several leukemias and lymphomas and was suggested to offer potential additional benefits in supressing T cell and inflammatory responses...

The monoclonal B-cell lymphocytosis (MBL) introduced as new entities in the 2008 WHO classification, are defined by circulating B-cell clone < 5.109/L without organomegaly and previous and/or simultaneous lymphoproliferative disorders. The MBL were subclassified in MBL CLL type (the most frequent), MBL atypical CLL type and MBL non-CLL type (rarely reported in literature). Here the clinic, cytologic, immunologic and genetic features of MBL non-CLL type were described from a series of 34 cases. As previously reported, present cases presented immunologic and genetic similarities to MZL and could be associated to the new proposed entity CBL-MZ (clonal B-cell lymphocytosis of marginal zone origin)...

Hypogammaglobulinemia (HGG) is a frequent finding in patients with hematological malignancies, and is commonly described in chronic lymphocytic leukemia (CLL) before or after treatment. We reviewed published literature available online in the last thirty years through Medline search of indexed articles focusing on the main differences and advantages of the products now available on the market, namely intravenous Ig (IVIg) and subcutaneous Ig (SCIg) preparations. IgRT is effective and safe in the prophylaxis of infections in a selected group of patients with CLL and hypogammaglobulinemia and is therefore a valuable tool for clinicians in the everyday management of infectious risk...

Large granular lymphocyte leukemia (LGLL) is a chronic lymphoproliferative disorder characterized by the proliferation of T or NK cytotoxic cells in the peripheral blood, the spleen and the bone marrow. Neutropenia leading to recurrent infections represents the main manifestation of LGLL. One specificity of LGLL is its frequent association with auto-immune disorders, among them first and foremost rheumatoid arthritis, and other hematologic diseases, including pure red cell aplasia and bone marrow failure. The large spectrum of manifestations and the classical indolent course contribute to the diagnosis difficulties and the frequency of underdiagnosed cases...

BACKGROUND: Every bout of exercise mobilizes and redistributes large numbers of effector lymphocytes with a cytotoxic and tissue migration phenotype. The frequent redistribution of these cells is purported to increase immune surveillance and play a mechanistic role in reducing cancer risk and slowing tumor progression in physically active cancer survivors. Our aim was to provide the first detailed single cell transcriptomic analysis of exercise-mobilized lymphocytes and test their effectiveness as a donor lymphocyte infusion (DLI) in xenogeneic mice engrafted with human leukemia...