Impact of the tumor microenvironment on prognosis in follicular lymphoma is dependent on specific treatment protocols
TL;DR: It is suggestive that a dense infiltrate of FoxP3-positive T cells, dense and interfollicular infiltrate of CD68-positive macrophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being poor prognostic sign in fludarabine- treated patients.
Abstract: Background The clinical behavior of follicular lymphoma is largely determined by properties of the non-malignant tumor microenvironment. The precise nature of the cell populations is still unclear and published data on their prognostic significance are highly conflicting. This may be partly due to heterogeneous composition and tr eatments. Design and Methods Pre-treatment biopsy samples of patients with follicular lymphoma treated in an EORTC/BNLI trial comparing fludarabine to cyclophosphamide, vincristine and prednisone (CVP) chemotherapy could be retrieved for 61 patients in five Eur opean countries. Immunohistochemical investigations were performed to evaluate tumor cell characteristics, T-cell subsets, follicular dendritic cells and macrophages and associations with clinical outcome were studied. Results Some markers showed a homogeneous prognostic impact, while others had a different and sometimes opposite effect in the treatment arms. CD69 expression on tumor cells was a poor prognostic sign and an interfollicular infiltrate of FoxP3-positive T cells was a good prognostic sign irrespective of the treatment arm. It is suggestive that a dense infiltrate of FoxP3-positive T cells, a dense and interfollicular infiltrate of CD68-positive macr ophages and complete follicular dendritic meshworks were associated with a favorable time to progression in CVP-treated patients, while being a poor prognostic sign in fludarabine-treated patients. Conclusions Our results suggest that characteristic properties of the microenvironment in follicular lymphoma determines the responses to essentially different chemotherapeutic approaches. These data may provide an explanation for the highly conflicting r esults on immunohistochemical markers and the prognostic role of the microenvironment in follicular lymphoma reported thus far and lay the basis for the development of predictive assays to tailor treatment in patients with follicular lymphoma.
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TL;DR: The roles of mesenchymal stem/stromal cells (MSCs), lymphoma-associated macrophages (LAMs), dendritic cells, cytotoxic T cells, PD-1 expressing CD4+ tumor infiltrating lymphocytes (TILs), T-cells expressing markers of exhaustion such as TIM-3 and LAG-3, regulatory T Cells, and natural killer cells are described.
Abstract: Lymphoma microenvironment is a complex system composed of stromal cells, blood vessels, immune cells as well as extracellular matrix, cytokines, exosomes, and chemokines. In this review, we describe the function, localization, and interactions between various cellular components. We also summarize their contribution to lymphoma immunity in the era of immunotherapy. Publications were identified from searching Pubmed. Primary literature was carefully evaluated for replicability before incorporating into the review. We describe the roles of mesenchymal stem/stromal cells (MSCs), lymphoma-associated macrophages (LAMs), dendritic cells, cytotoxic T cells, PD-1 expressing CD4+ tumor infiltrating lymphocytes (TILs), T-cells expressing markers of exhaustion such as TIM-3 and LAG-3, regulatory T cells, and natural killer cells. While it is not in itself a cell, we also include a brief overview of the lymphoma exosome and how it contributes to anti-tumor effect as well as immune dysfunction. Understanding the cellular players that comprise the lymphoma microenvironment is critical to developing novel therapeutics that can help block the signals for immune escape and promote tumor surveillance. It may also be the key to understanding mechanisms of resistance to immune checkpoint blockade and immune-related adverse events due to certain types of immunotherapy.
29 citations
Cites background from "Impact of the tumor microenvironmen..."
...However, follow-up studies did not show compatible findings when immunohistochemical assays substituted gene expression analysis (24, 25)....
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TL;DR: Vascularity is associated with MC content and outcome in R-CHOP-treated FL patients, and a positive prognostic impact of VEGF mRNA expression on the outcome was found.
28 citations
TL;DR: It is demonstrated that tumor-infiltrating TFH specifically express functional IL-4 in FL, creating therefore an IL- 4-dependent TFH-B cell axis that could sustain FL pathogenesis and represent a new potential therapeutic target.
27 citations
Cites background from "Impact of the tumor microenvironmen..."
...Of note, the predictive value of microenvironment cell populations in FL is highly dependent on specific treatment protocols.(16,17) To draw a more complete picture of the influence of the microenvironment in FL, microarray analyses were performed and allowed to identify two specific molecular signatures associated with patient’s outcome independently of classical clinical features....
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TL;DR: Follicular dendritic cells in follicular lymphoma and types of non‐Hodgkin lymphoma show reduced expression of CD23, CD35 and CD54 but no association with clinical outcome.
Abstract: Jin M K, Hoster E, Dreyling M, Unterhalt M, Hiddemann W & Klapper W (2011) Histopathology 58, 586–592 Follicular dendritic cells in follicular lymphoma and types of non-Hodgkin lymphoma show reduced expression of CD23, CD35 and CD54 but no association with clinical outcome
Aims: Follicular dendritic cells (FDC) are specialized antigen-presenting cells found exclusively in the germinal centre (GC), which can be detected in B cell non-Hodgkin lymphomas (NHL) as reactive bystander cells. Recently, gene expression profiling has revealed that FDC networks might be associated with clinical outcome in follicular lymphoma. The aim was to characterize FDC in NHL and to evaluate a possible association with outcome in follicular lymphoma.
Methods and results: The extent and immunophenotype of FDC was determined semi-quantitatively in reactive GC and NHL (follicular lymphoma, angioimmunoblastic T cell lymphoma, mantle cell lymphoma) using fluorescence double staining and digital image analysis. In all NHL tested CD23 and CD35 and CD54 were expressed at relatively low levels on FDC, comparable to FDC found in the dark zone of the GC. However, the extent of FDC networks did not correlate with the clinical outcome of 102 patients with follicular lymphomas treated within a prospectively randomized trial.
Conclusions: FDC found in different types of NHL show quantitatively reduced expression of several proteins, suggesting that there are functional differences between FDC in normal GC and NHL. The extent of the FDC networks in follicular lymphoma is not useful as a prognostic marker.
26 citations
TL;DR: It is suggested that the identified subtype-specific genes could reflect different phases of wound healing, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing.
Abstract: Classical Hodgkin's lymphoma (cHL), although a malignant disease, has many features in common with an inflammatory condition. The aim of this study was to establish the molecular characteristics of the two most common cHL subtypes, nodular sclerosis (NS) and mixed cellularity (MC), based on molecular profiling and immunohistochemistry, with special reference to the inflammatory microenvironment. We analysed 44 gene expression profiles of cHL whole tumour tissues, 25 cases of NS and 19 cases of MC, using Affymetrix chip technology and immunohistochemistry. In the NS subtype, 152 genes showed a significantly higher expression, including genes involved in extracellular matrix (ECM) remodelling and ECM deposition similar to wound healing. Among these were SPARC, CTSK and COLI. Immunohistochemistry revealed that the NS-related genes were mainly expressed by macrophages and fibroblasts. Fifty-three genes had a higher expression in the MC subtype, including several inflammation-related genes, such as C1Qα, C1Qβ and CXCL9. In MC tissues, the C1Q subunits were mainly expressed by infiltrating macrophages. We suggest that the identified subtype-specific genes could reflect different phases of wound healing. Our study underlines the potential function of infiltrating macrophages in shaping the cHL tumour microenvironment.
25 citations
Cites background from "Impact of the tumor microenvironmen..."
...Our data suggest that most macrophages in the NS subtype might display the so-called M2 phenotype because of their ECM remodelling profile, whereas those infiltrating MC tumours are similar to cytotoxic macrophages found in other types of lymphomas (Dave et al, 2004; de Jong et al, 2009)....
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References
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TL;DR: The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide to help provide an optimal treatment option for patients with follicular lymphoma.
1,459 citations
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
"Impact of the tumor microenvironmen..." refers background in this paper
...From a biological point of view, the clinical behavior of FL is determined principally by the tumor microenvironment rather than by inherent properties of the tumor cells themselves.(5-7) Specific T-cell and accessory cell populations, including macrophages and follicular dendritic cells, have been reported to have an influence on overall and/or progression-free survival, either as a poor or a good prognostic parameter....
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...haematologica | 2009; 94(1) | 75 | tance of the microenvironment in the clinical behavior of FL.(5-7) The precise nature of the relevant cell populations is still unclear, and published data on the prognostic significance of cell populations, including T-cell subsets, macrophages and follicular dendritic cells, are conflicting....
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Journal Article•
TL;DR: The population of CD4+CD25+ immunoregulatory cells is characterized and it is demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells.
Abstract: Thymectomy of susceptible strains of mice on day 3 of life results in a spectrum of organ-specific autoimmunity that can be prevented by reconstitution of the thymectomized animals early in life with normal adult lymphocytes. The effectors and suppressors of autoimmunity in this model have been convincingly shown to be CD4+ T cells. It has been demonstrated recently that the regulatory CD4+ T cells that prevent disease coexpress CD25. We have further characterized the population of CD4+CD25+ immunoregulatory cells and demonstrated that they can suppress not only the induction of disease post-thymectomy, but can also efficiently suppress disease induced by cloned autoantigen-specific effector cells. Furthermore, the CD4+CD25+ T cells appear to be members of a unique lineage of regulatory T cells, as the induction of CD25 expression on a monospecific population of T cells derived from TCR transgenic SCID mice did not result in suppression of post-thymectomy autoimmunity. In addition, the TCR transgenic SCID mice were highly susceptible to autoimmune disease induced by the cloned line of autoantigen-specific effectors, while normal mice were relatively resistant. The capacity of the cloned line to transfer disease to nu/nu recipients could be inhibited by normal spleen cell populations containing CD4+CD25+ cells and by purified CD4+CD25+ cells. Although the target Ag(s) and mechanism of action of the CD4+CD25+ T cells remain to be determined, it is likely that they also play an important role in modulating other autoimmune diseases that are mediated by activation of "ignorant" self-reactive T cells present in the normal peripheral lymphocyte pool.
927 citations
"Impact of the tumor microenvironmen..." refers background in this paper
...It has been shown that fludarabine has a rather specific effect on FoxP3-positive regulatory T cells in patients with B-cell chronic lymphocytic leukemia, in that both the frequency and the inhibitory functions of these cells are reduced after treatment.(23-25) Very likely, interference with the tumor microenvironment may result in different responses depending on the specific role of the microenvironment in a specific class of FL....
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TL;DR: This is the first report demonstrating that CY, in addition to decreasing cell number, inhibits the suppressive capability of T(REGs), and the relevance of the loss of suppressor functionality and the changes in gene expression are discussed.
889 citations
"Impact of the tumor microenvironmen..." refers background in this paper
...Similar effects of cyclophosphamide have been shown on regulatory T cells too.(26)...
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TL;DR: The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide to help provide an optimal treatment option for patients with follicular lymphoma.
Abstract: Although numerous treatment approaches are proposed for patients with follicular lymphoma, criteria to help in choosing a treatment for a given patient and for comparing trial results are lacking. Several retrospective studies have analyzed prognostic factors, but their conclusions rely on limited numbers of patients treated during long periods, and their results are discordant. The Follicular Lymphoma International Prognostic Index was designed from the data recorded over 8 years of nearly 5000 patients registered worldwide. Five factors are used (age, Ann Arbor stage, number of nodal sites, serum lactate dehydrogenase level, and hemoglobin level) to build a three-category index. This index, together with new biologic markers such as gene profiling and proteomics, could help provide an optimal treatment option for patients with follicular lymphoma.
863 citations