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: There is evidence that addition of IFN as maintenance therapy for FL improves progression-free survival and a net benefit for overall survival is less evident.
Abstract: Background Indolent non-Hodgkin's lymphoma, in particular follicular lymphoma (FL), is characterized by multiple remissions and relapses. Several studies have used interferon-alpha (IFN) to control this disease, both as induction and as maintenance therapy. It is not yet clear whether IFN can be associated with a survival benefit although it may prolong progression-free survival. Objectives To determine the effects of IFN in the maintenance therapy of FL. Search strategy We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, Issue 4, 2008), MEDLINE (1966 to 2008), DARE (1990 to 2008), SCOPUS (searched December 2008) and Current Contents (1975 to 2008). . Selection criteria Randomised controlled trials of IFN versus no intervention or placebo, or IFN plus chemotherapy versus chemotherapy alone, in a maintenance setting in patients with non-Hodgkin's FL. Primary outcomes were overall survival and progression-free survival. Data collection and analysis Three review authors independently assessed trial quality and extracted data. We contacted study authors for additional information. We collected adverse events information from the trials. Main results We included eight trials (1563 patients). The drug was IFN alfa-2b in six trials and alfa-2a in two. Trials were heterogeneous in terms of diagnosis of FL, using several classification systems. IFN had been compared with placebo/no intervention in five trials and other chemotherapy in three. The effect of IFN was similar to that of placebo on overall survival (hazard ratio (HR) 0.90, 95% CI 0.61 to 1.34) whereas IFN was more effective when added to chemotherapy (HR 0.68, 95% confidence interval (CI) 0.52 to 0.90). Considering IFN versus all comparators, IFN was effective in prolonging progression-free survival (HR 0.66, 95% CI 0.57 to 0.77) and overall survival (fixed effects HR 0.79, 95% CI 0.67 to 0.94, I(2) = 52%). After adjustment for heterogeneity this statistically significance disappeared (random effects HR 0.82, 95% CI 0.63 to 1.08). Toxicity and patients lost to follow up were significantly higher in the IFN groups. Authors' conclusions There is evidence that addition of IFN as maintenance therapy for FL improves progression-free survival. A net benefit for overall survival is less evident. In the included studies, IFN was associated with significant toxicities that may have a major impact on a patient's quality of life.
32 citations
TL;DR: It is demonstrated that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition.
Abstract: Follicular lymphoma (FL) frequently transforms into the more aggressive diffuse large B cell lymphoma (DLBCL-tr), but no protein biomarkers have been identified for predictive or early diagnosis. Gene expression analyses have identified genes changing on transformation but have failed to be reproducible in different studies, reflecting the heterogeneity within the tumor tissue and between tumor samples. Gene expression analyses on Affymetrix Human Genome U133 Plus 2.0 arrays were performed, using flow cytometry sorted tumor cells derived from FL and transformed DLBCL. To identify molecular targets associated with the transformation, subsequent immunohistochemistry (IHC) analyses of the corresponding proteins were performed. Using highly purified cells, this study identified 163 genes, which were significantly deregulated during the transformation in a majority of cases. Among the upregulated transcripts, 13 genes were selected for validation using IHC, based on the availability of commercial antibodies, and galectin-3 and NEK2 proteins specifically identify DLBCL-tr, when compared with FL. We demonstrate that by purifying tumor cells through cell sorting, thereby reducing the heterogeneity due to infiltrating cells, it was possible to identify distinct differences between tumor entities rather than variations due to cellular composition. Galectin-3 and NEK2 both identified a subgroup of DLBCL-tr, and the function of these protein markers also suggests a biological role in the transformation process.
32 citations
Journal Article•
TL;DR: Strategies that both enhance an effective antitumor response and reverse immunosuppression and dysfunction will be essential in the development of effective immunotherapeutic approaches in this disease.
Abstract: Like other B-cell lymphomas, the development and progression of follicular lymphoma (FL) involves complex interactions between the neoplastic B cells and the surrounding microenvironment. Malignant B cells can manipulate the microenvironment by skewing the differentiation of immune cells, attracting regulatory T cells or suppressive monocytes, or secreting cytokines that promote an immunosuppressive environment. The importance of the microenvironment in FL has been demonstrated using methodologies such as gene expression profiling, which has shown that the nature of the tumor microenvironment predicts survival in patients with FL and may influence the response to immunotherapy and risk of transformation. Strategies that both enhance an effective antitumor response and reverse immunosuppression and dysfunction will be essential in the development of effective immunotherapeutic approaches in this disease.
32 citations
TL;DR: Evaluation of blood ANKC may be a useful indicator of outcome in previously untreated FL patients, and was associated with inferior overall survival by univariate analysis and trended to significance in multivariable analysis with ACD4C.
31 citations
TL;DR: There is an active interaction between follicular cells and the microenvironment that determines the clinical behavior, prognosis, and response to specific treatment protocols, and it is likely that the tumor microenvironment itself may become a target of therapy, or that therapy might be tailored based upon the specific immune microenvironment of the biopsy.
Abstract: Purpose of review Although outcomes for patients with follicular lymphoma have improved with chemoimmunotherapy, the disease remains incurable. There is a wide variation in survival, and although the Follicular Lymphoma International Prognostic Index helps to risk-stratify patients, there is a need for robust biomarkers of disease outcome. Most patients will succumb to the emergence of chemoresistance or transformation to diffuse large B-cell lymphoma and there is a need for new treatment approaches in this disease. Recent findings Gene expression profiling studies and immunohistochemical analyses have highlighted the importance of the tumor microenvironment in follicular lymphoma. There have, however, been conflicting results regarding the prognostic significance of specific subsets of immune cells in follicular lymphoma. Recent studies have highlighted the interaction of specific treatment protocols and the immune environment on outcome. We are now beginning to uncover the molecular basis of the complex interactions that occur between follicular lymphoma cells and the immune microenvironment. Summary There is an active interaction between follicular cells and the microenvironment that determines the clinical behavior, prognosis, and response to specific treatment protocols. As we have a more complete understanding of this complex interaction it is the likely that the tumor microenvironment itself may become a target of therapy, or that therapy might be tailored based upon the specific immune microenvironment of the biopsy.
31 citations
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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