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Activation of Th1 Immunity Within the Tumor Microenvironment is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia

ABSTRACT: Activation of Th1 Immunity Within the Tumor Microenvironment is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia

PROVIDER: PRJNA449556 | ENA |

REPOSITORIES: ENA

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Activation of Th1 Immunity Within the Tumor Microenvironment is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia

Project description:Immune stimulation contributes to lenalidomide’s anti-tumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T-cell function in vitro. Whether T-cell activation is required for clinical response to lenalidomide remains unclear. Here we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with anti-tumor response. Within days of starting lenalidomide, CD3+ cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pre-treatment and on-treatment lymph node biopsies revealed upregulation of IFN and many of its target genes in response to lenalidomide. The IFNγ-mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of T-cell receptor genes revealed decreasing diversity of the T-cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T-cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.

2018-07-25 | GSE112953 | GEO

Activation of Th1 Immunity within the Tumor Microenvironment Is Associated with Clinical Response to Lenalidomide in Chronic Lymphocytic Leukemia.

Project description:Immune stimulation contributes to lenalidomide's antitumor activity. Chronic lymphocytic leukemia (CLL) is characterized by the accumulation of mature, autoreactive B cells in secondary lymphoid tissues, blood, and bone marrow and progressive immune dysfunction. Previous studies in CLL indicated that lenalidomide can repair defective T cell function in vitro. Whether T cell activation is required for clinical response to lenalidomide remains unclear. In this study, we report changes in the immune microenvironment in patients with CLL treated with single-agent lenalidomide and associate the immunologic effects of lenalidomide with antitumor response. Within days of starting lenalidomide, T cells increased in the tumor microenvironment and showed Th1-type polarization. Gene expression profiling of pretreatment and on-treatment lymph node biopsy specimens revealed upregulation of IFN-? and many of its target genes in response to lenalidomide. The IFN-?-mediated Th1 response was limited to patients achieving a clinical response defined by a reduction in lymphadenopathy. Deep sequencing of TCR genes revealed decreasing diversity of the T cell repertoire and an expansion of select clonotypes in responders. To validate our observations, we stimulated T cells and CLL cells with lenalidomide in culture and detected lenalidomide-dependent increases in T cell proliferation. Taken together, our data demonstrate that lenalidomide induced Th1 immunity in the lymph node that is associated with clinical response.

| S-EPMC6143435 | biostudies-literature

Lenalidomide With or Without Rituximab in Treating Patients With Progressive or Relapsed Chronic Lymphocytic Leukemia, Small Lymphocytic Lymphoma, Prolymphocytic Leukemia, or Non-Hodgkin Lymphoma Previously Treated With Donor Stem Cell Transplant

Project description:This phase II trial studies how well giving lenalidomide with or without rituximab works in treating patients with progressive or relapsed chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), prolymphocytic leukemia (PLL), or non-Hodgkin lymphoma (NHL). Biological therapies, such as lenalidomide, may stimulate the immune system in different ways and stop cancer cells from growing. Monoclonal antibodies, such as rituximab, can block cancer growth in different ways. Some block the ability of cancer to grow and spread. Others find cancer cells and help kill them or carry cancer-killing substances to them. Giving lenalidomide together with or without rituximab may kill more cancer cells.

| 2111714 | ecrin-mdr-crc

Gene expression profiles of nurse-like cells (NLCs) generated in vitro from chronic lymphocytic leukemia in presence of lenalidomide

Project description:NLCs were generated in vitro by culturing PBMCs from CLL patients for 10 days with/without the addition of 0.5 ÂµM lenalidomide. Then, nonadherent cells were removed by vigorous pipetting and the remaining adherent cells were harvested for analyses. We inspected the whole-genome gene expression profiles of NLCs (control sample vs. lenalidomide-treated sample) derived from 4 CLL patients by microarray. Supervised analysis identified 584 genes differentially expressed upon lenalidomide treatment, 352 up-regulated and 232 down-regulated (p<0.05). RNA was extracted with the RNeasy Plus Mini kit (Qiagen, Valencia, CA, USA). Large-scale gene expression profiling (GEP) was performed by hybridizing RNA from NLCs treated or not with lenalidomide 0.5 ÂµM for 10 days (n=4) on 4X44K Whole Human Genome Microarray (Agilent Technologies, Palo alto, CA). Genes were defined as differentially expressed between groups (NLCs CTRL vs. NLCs LENALIDOMIDE) at p<0.05 (paired t-test) and fold change Â± 1.5 by using Gene Spring GX v12.6 (Agilent) software.

2014-11-24 | E-GEOD-57861 | biostudies-arrayexpress

Gene expression profiles of nurse-like cells (NLCs) generated in vitro from chronic lymphocytic leukemia in presence of lenalidomide

Project description:NLCs were generated in vitro by culturing PBMCs from CLL patients for 10 days with/without the addition of 0.5 µM lenalidomide. Then, nonadherent cells were removed by vigorous pipetting and the remaining adherent cells were harvested for analyses. We inspected the whole-genome gene expression profiles of NLCs (control sample vs. lenalidomide-treated sample) derived from 4 CLL patients by microarray. Supervised analysis identified 584 genes differentially expressed upon lenalidomide treatment, 352 up-regulated and 232 down-regulated (p<0.05).

2014-11-24 | GSE57861 | GEO

Tumor microenvironment impairs Th1 cell differentiation through alternative splicing modifications

Project description:Tumor microenvironment impairs Th1 cell differentiation through alternative splicing modifications

| PRJNA556640 | ENA

Gene expression profiles of 16 relapsed/refractory CLL patients treated with lenalidomide in a phase II clinical trial

Project description:The aim of the study is to identify differentially expressed genes between chronic lymphocytic leukemia (CLL) patients who will respond to lenalidomide treatment and non responsive patients. We performed a whole genome gene-expression analysis of pre-treatment samples collected from 16 CLL patients included in a phase II clinical trial. The pre-treatment sample comprises purified CD19 cells from peripheral blood. Ten (37%) patients achieved partial responses (PR) and were classified as responders (R), 2 (7%) stable diseases (SD) and 4 (15%) progressive diseases (PD) and were classified as non responders (NR). Supervised analysis identified 78 genes up-regulated and 119 genes down-regulated in R compared with NR (Fold change [FC]≥2, p<0.01, Figure 4). Different expression levels of genes involved in interferon (INF) and Wnt signaling pathways characterized patients who will respond to lenalidomide. In particular, R showed a 23-fold increase in Wnt inhibitor Shisa homolog 3 (SHISA3), whereas a decrease of WISP3, CDH4, HOXB7 and WNT10A. Moreover, leukemic cells collected from R down-regulated interferon-induced proteins (IFI44, -6.6; IFI44L, -9.3; IFIT2, -2) and STAT1 (-2.4 fold change). NR group up-regulated lipoprotein lipase (LPL, +7.5). The baseline expression levels of cereblon (CRBN) were not dissimilar between R and NR subsets

2017-10-12 | GSE87910 | GEO

Effect of Lenalidomide on human macrophages.

Project description:Lenalidomide, an IMiD® immunomodulatory agent used for the treatment of multiple myeloma (MM),is believed to target the stromal support, but its precise mechanism on the phenotype or the effector functions of macrophages is still unclear. To investigate the effect of lenalidomide on macrophages, M-CSF generated macrophages were treated with Lenalidomide and analyzed by RNA-seq.

2021-01-23 | GSE165332 | GEO

Molecular characterization of the microenvironment in CLL-like monoclonal B cell lymphocytosis and early stage chronic lymphocytic leukemia

Project description:Several studies have demonstrated an impaired function of the microenvironment in chronic lymphocytic leukemia (CLL), contributing to immune evasion of tumor cells and disease progression. However, in CLL-like monoclonal B cell lymphocytosis (MBL) studies are scarce. Herein, a comprehensive characterization of the microenvironment in 59 MBL, 56 early stage CLL and 31 healthy controls was conducted. Gene expression arrays and qRT-PCR were performed on RNA from CD4+ peripheral blood cells; serum cytokines were measured by immunoassays and proteomic studies; and flow cytometry was applied to evaluate peripheral blood cytotoxic, Th1, exhausted and effector CD4+ T cells, besides monocytic CD14, CD4 and HLA-DR expression. MBL and early stage CLL showed a similar upregulation of cytotoxic and Th1-related genes, expanded perforin+ and CXCR3+ CD4+ T cells as well as PD1+ CD4+ T cells compared to controls. However, a strong inflammatory response was only identified in MBL: enhanced phagocytosis, pattern recognition receptors, IL8, HMGB1, TREM1 and acute response signaling pathways, along with increased levels of proinflammatory cytokines (remarkably IL8, IFN? and TNF?). Of note, this inflammatory drive was decreased in early stage CLL: diminished proinflammatory cytokines including IFN?, decreased IL8 signaling pathway and lower monocytic HLA-DR expression compared to MBL. Besides, this inflammation was especially reduced in IGHV mutated CLL, involving a decrease of the proinflammatory HMGB1 signaling pathway. These novel findings reveal a different pathophysiology between MBL and CLL, paving the way for the development of pre-emptive immunotherapies with optimal benefits at MBL and early stage CLL, before intense immune exhaustion.

2020-03-29 | GSE125791 | GEO

Unveiling key players in the Chronic Lymphocytic Leukemia (CLL)-microenvironment interplay

Project description:Unveiling key players in the Chronic Lymphocytic Leukemia (CLL)-microenvironment interplay

| PRJNA488214 | ENA