Follicular lymphoma cells induce T-cell immunologic synapse dysfunction that can be repaired with lenalidomide: implications for the tumor microenvironment and immunotherapy
TL;DR: In this article, the authors identify impaired T-cell immunologic synapse formation as an active immunosuppressive mechanism in follicular lymphoma (FL) and diffuse large B-cell lymphoma(DLBCL).
About: This article is published in Blood.The article was published on 2009-11-19 and is currently open access. It has received 225 citations till now. The article focuses on the topics: T cell & Interleukin 21.
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TL;DR: A fundamental understanding of interactions between tumour cells and non-malignant cells gives insight into the pathogenesis of most B cell lymphomas and identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
Abstract: B cell lymphomas are cancers that arise from cells that depend on numerous highly orchestrated interactions with immune and stromal cells in the course of normal development. Despite the recent focus on dissecting the genetic aberrations within cancer cells, it has been increasingly recognized that tumour cells retain a range of dependence on interactions with the non-malignant cells and stromal elements that constitute the tumour microenvironment. A fundamental understanding of these interactions gives insight into the pathogenesis of most B cell lymphomas and, moreover, identifies novel therapeutic opportunities for targeting oncogenic pathways, both now and in the future.
392 citations
TL;DR: The results using human CLL as a model cancer establish a novel evasion mechanism whereby malignant cells exploit multiple inhibitory ligand signaling to down-regulate small GTPases and lytic synapse function in global T-cell populations.
331 citations
TL;DR: There is a need to develop novel therapies for relapsed/refractory diffuse large B‐cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response and it is currently unknown if response rates differ between patients with different DLBCL subtypes.
Abstract: BACKGROUND:
There is a need to develop novel therapies for relapsed/refractory diffuse large B-cell lymphoma (DLBCL) and to identify biomarkers predictive for therapeutic response. Lenalidomide was previously shown to induce an overall response rate (ORR) of 28% in patients with relapsed/refractory DLBCL. It is currently unknown if response rates differ between patients with different DLBCL subtypes.
METHODS:
The authors retrospectively evaluated clinical outcomes of patients with germinal center B-cell–like versus nongerminal center B-cell–like DLBCL treated with salvage lenalidomide at 4 academic institutions.
RESULTS:
Forty patients with relapsed/refractory DLBCL were included (24 men; 16 women; median age, 66 years; median of 4 prior treatments, including rituximab chemotherapy). Patients were classified as germinal center B-cell–like (n = 23) or nongerminal center B-cell–like (n = 17) DLBCL according to the Hans algorithm. The subgroups were similar in terms of stage, international prognostic index score, prior number of treatments, and rituximab resistance. A significant difference in clinical response to lenalidomide was observed in nongerminal center B-cell–like versus germinal center B-cell–like patients. ORR was 52.9% versus 8.7% (P = .006); complete response rate was 23.5% versus 4.3%. Median progression-free survival was 6.2 versus 1.7 months (P = .004), although no difference in OS was observed between nongerminal center B-cell–like and germinal center B-cell–like DLBCL patients.
CONCLUSIONS:
The data suggest that the 2 major subgroups of patients with DLBCL (germinal center B cell and nongerminal center B cell) have different antitumor responsiveness to lenalidomide in the relapsed/refractory setting. A large international trial (NCT01197560) has been opened to enrollment in an attempt to prospectively validate these retrospective observations. Cancer 2011;. © 2011 American Cancer Society.
301 citations
Cites background from "Follicular lymphoma cells induce T-..."
...This finding adds credibility to the concept of 2 different molecular, biological, and clinical subtypes of DLBCL.20 Abbreviations: CI, confidence interval; CR, complete response; GCB, germinal left B-cell–like; ORR, overall response rate; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; PR, partial response; SD, stable disease....
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...Bortezomib and lenalidomide are known to both inhibit NF-KB activity in vitro, and activated B-cell–like DLBCL is known to be driven by constitutive activation of NF-KB,28 which supports the hypothesis that targeting the NF-KB-pathway can be clinically relevant in patients with nongerminal center B-cell– like (or at least activated B-cell–like subtype) DLBCL....
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...Differences in endpoints were com- pared between patients with germinal center B-cell–like and nongerminal center B-cell–like DLBCL....
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...Lenalidomide was previously shown to induce an overall response rate (ORR) of 28% in patients with relapsed/refractory DLBCL....
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...Recently, lenalidomide was found to modulate T-cell functions and repair F-actin–mediated T-cell immune synapses against primary tumor cells in chronic lymphocytic leukemia, follicular lymphoma, and DLBCL.(17)...
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TL;DR: The cellular and molecular interactions between B cell lymphoma/leukemia cells and their microenvironment, and the therapeutic targets that are emerging, focusing on small molecule inhibitors that are targeting B cell receptor-associated kinases SYK, BTK, and PI3Ks, as well as on immunomodulatory agents and T cell mediated therapies are summarized.
261 citations
TL;DR: Crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.
Abstract: The hallmark t(14;18)(q32;q21) in follicular lymphoma (FL) results in constitutive overexpression of the BCL2 protein, allowing B cells to abrogate the default germinal center apoptotic program. Most tumors are characterized by recurrent secondary genetic alterations including genomic gains, losses, and mutations, some providing a growth advantage, including alterations in MLL2, EPHA7, TNFRSF14, and EZH2. The sequence in which these events occur and how they contribute to progression and ultimately to transformation is unclear. Lastly, crosstalk between neoplastic B cells and non-neoplastic immune and stromal cells in the microenvironment plays an important role in sustaining tumor cell growth, cultivating immune privilege, and promoting transformation.
257 citations
Cites background from "Follicular lymphoma cells induce T-..."
...For example, immune synapses between malignant B cells and T cells are defective, although CD8+ CTLs have been shown to localize at the follicle border and enter into contact with tumor cells (85, 86)....
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References
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National Institutes of Health1, University of Würzburg2, University of British Columbia3, University of Nebraska Medical Center4, University of Rochester5, Oregon Health & Science University6, University of Arizona7, Fred Hutchinson Cancer Research Center8, University of Oslo9, St Bartholomew's Hospital10, University of Barcelona11
TL;DR: The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
Abstract: background Patients with follicular lymphoma may survive for periods of less than 1 year to more than 20 years after diagnosis. We used gene-expression profiles of tumor-biopsy specimens obtained at diagnosis to develop a molecular predictor of the length of survival. methods Gene-expression profiling was performed on 191 biopsy specimens obtained from patients with untreated follicular lymphoma. Supervised methods were used to discover expression patterns associated with the length of survival in a training set of 95 specimens. A molecular predictor of survival was constructed from these genes and validated in an independent test set of 96 specimens. results Individual genes that predicted the length of survival were grouped into gene-expression signatures on the basis of their expression in the training set, and two such signatures were used to construct a survival predictor. The two signatures allowed patients with specimens in the test set to be divided into four quartiles with widely disparate median lengths of survival (13.6, 11.1, 10.8, and 3.9 years), independently of clinical prognostic variables. Flow cytometry showed that these signatures reflected gene expression by nonmalignant tumor-infiltrating immune cells. conclusions The length of survival among patients with follicular lymphoma correlates with the molecular features of nonmalignant immune cells present in the tumor at diagnosis.
1,336 citations
TL;DR: The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte–monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting.
Abstract: Lymphomas express a tumor-specific antigen which can be targeted by cancer vaccination We evaluated the ability of a new idiotype protein vaccine formulation to eradicate residual t(14;18)+ lymphoma cells in 20 patients in a homogeneous, chemotherapy-induced first clinical complete remission All 11 patients with detectable translocations in their primary tumors had cells from the malignant clone detectable in their blood by PCR both at diagnosis and after chemotherapy, despite being in complete remission However, 8 of 11 patients converted to lacking cells in their blood from the malignant clone detectable by PCR after vaccination and sustained their molecular remissions Tumor-specific cytotoxic CD8+ and CD4+ T cells were uniformly found (19 of 20 patients), whereas antibodies were detected, but apparently were not required for molecular remission Vaccination was thus associated with clearance of residual tumor cells from blood and long-term disease-free survival The demonstration of molecular remissions, analysis of cytotoxic T lymphocytes against autologous tumor targets, and addition of granulocyte-monocyte colony-stimulating factor to the vaccine formulation provide principles relevant to the design of future clinical trials of other cancer vaccines administered in a minimal residual disease setting
582 citations
TL;DR: Results demonstrate that autologous immunoglobulin idiotype can be formulated into an immunogenic, tumor-specific antigen in humans with B-cell lymphoma, and they provide the background for large-scale trials of active specific immunotherapy of this disease.
Abstract: Background. The idiotypic determinants of the surface immunoglobulin of a B-cell lymphoma can serve as a clonal tumor-specific marker, which may have implications for immunotherapy. We sought to determine whether idiotype-specific immune responses against this autologous antigen could be induced in patients with B-cell lymphoma. Methods. Nine patients were selected who had minimal residual disease or a complete remission after chemotherapy. Each received a series of subcutaneous injections of the immunoglobulin derived from his or her tumor cells (immunoglobulin-idiotype protein), which had been conjugated to a protein carrier and mixed with an immunologic adjuvant. Results. In seven of the nine patients the injections induced sustained idiotype-specific immunologic responses of the humoral type (two patients), the cell-mediated type (four patients), or both (one patient). The use of an adjuvant was essential for these immune responses. The induced antibodies bound specifically to autologous immu...
571 citations
TL;DR: Impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia exhibiting defective immunological synapse formation with APCs is demonstrated and repair of immune synapse defects is identified as an essential step in improving cancer immunotherapy approaches.
Abstract: Cancer is associated with immune deficiency, but the biologic basis of this is poorly defined. Here we demonstrate that impaired actin polymerization results in CD4+ and CD8+ T cells from patients with chronic lymphocytic leukemia (CLL) exhibiting defective immunological synapse formation with APCs. Although this synapse dysfunction was in part a result of the CLL cells having poor APC function, defective actin polymerization was also identified in T cells from patients with CLL. We further demonstrate that, following contact with CLL cells, defects in immune synapse formation were induced in healthy allogeneic T cells. This required direct contact and was inhibited by blocking adhesion molecules on CLL B cells. In T cells from patients with CLL and in T cells from healthy individuals that had been in contact with CLL cells, recruitment of key regulatory proteins to the immune synapse was inhibited. Treatment of autologous T cells and CLL cells with the immunomodulating drug lenalidomide resulted in improved synapse formation. These results define what we believe to be a novel immune dysfunction in T cells from patients with CLL that has implications for both autologous and allogeneic immunotherapy approaches and identifies repair of immune synapse defects as an essential step in improving cancer immunotherapy approaches.
552 citations
TL;DR: CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm that predicts that reducing tumor- driven immune suppression will be clinically beneficial.
Abstract: Tumors express antigens that should induce immune-mediated rejection, but spontaneous rejection of established tumors is rare. Recent work demonstrates that one reason for the lack of tumor rejection is that tumors actively defeat host immunity. This concept forces us to rethink current approaches to harnessing potent, specific host immunity to battle cancer, most of which are based on the paradigm that inducing more antitumor immune cells alone is therapeutic. However, as I discuss in this Personal Perspective, a newer paradigm predicts that reducing tumor-driven immune suppression will be clinically beneficial. CD4+CD25+ Tregs are one mechanism of tumor-driven immune evasion that provide prototypical targets for testing novel anticancer treatment strategies within the newer paradigm.
551 citations