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 results show that SIRPα expression delineates unique subsets of intratumoral Mo/MΦs with differing prognostic importance, and Clinically, increased numbers of CD14+SirPαhi cells were associated with an inferior survival in FL, and increased number of the CD14−SIRP αlow subset appeared to correlate with a better survival.
Abstract: Signal regulatory protein-α (SIRPα) is a key member of the “do-not-eat-me” signaling pathway, but its biological role and clinical relevance in B-cell NHL is relatively unknown. Using biopsy specimens from follicular lymphoma (FL), we identified three subsets (CD14+SIRPαhi, CD14−SIRPαlow, and CD14−SIRPαneg) of monocyte/macrophages (Mo/MΦ) based on CD14 and SIRPα expression. CD14+SIRPαhi cells expressed common Mo/MΦ markers; exhibited characteristic differentiation, migration, and phagocytosis; and suppressed T-cell function. CD14−SIRPαlow cells expressed fewer typical Mo/MΦ markers; migrated less and phagocytosed tumor cells less efficiently; and stimulated rather than suppressed T-cell function. Interestingly, the CD14−SIRPαneg subset expressed distinct Mo/MΦ markers compared to the other two subsets; had limited ability to migrate and phagocytose; but stimulated T-cell function. When using SIRPα-Fc to block the interaction between SIRPα and CD47, alone or in combination with rituximab, phagocytosis of tumor cells was differentially increased in the three Mo/MΦ subsets. Clinically, increased numbers of CD14+SIRPαhi cells were associated with an inferior survival in FL. In contrast, increased numbers of the CD14−SIRPαlow subset appeared to correlate with a better survival. Taken together, our results show that SIRPα expression delineates unique subsets of intratumoral Mo/MΦs with differing prognostic importance.
35 citations
TL;DR: Gastric MALT lymphomas have a number of Treg cells more similar to chronic gastritis than to DLBCL and patients with higher number of tumor infiltrating FOXP3+ cells at study entry seem to have better response to antibiotics.
Abstract: Purpose: FOXP3+ regulatory T cells (Treg) play an essential role in modulating host responses to tumors and infections. The role of these cells in the pathogenesis of MALT lymphomas remains unknown. The aims of the study were to quantify the number of infiltrating FOXP3+ and CD3+ cells in patients with gastric MALT lymphoma at diagnosis and to study kinetics of these cells and CD20+ tumor cells after treatment and during long-term follow-up. Methods: FOXP3+, CD3+ and CD20+ cells were analyzed by immunohistochemistry and the number of cells was quantified using a micrometric ocular. Samples of 35 patients with gastric MALT lymphoma at diagnosis and after treatment were included. Diagnostic samples were compared to 19 cases of chronic gastritis and diffuse large B-cell lymphoma (DLBCL) of the stomach. Results: The median number of FOXP3+ infiltrating cells was higher (27 cells/cm 2 ) in gastric MALT patients than in DLBCL (10 cells; p=0.162) but similar to chronic gastritis (20 cells; p=0.605). No characteristic or specific distribution pattern of infiltrating FOXP3+ cells was found. Gastric MALT lymphoma patients responding to bacterial eradication therapy had higher number of FOXP3+ cells at study entry. Kinetics of both infiltrating FOXP3+ cells and tumor CD20+ cells were strongly dependent on the treatment administered. Discussion: Gastric MALT lymphomas have a number of Treg cells more similar to chronic gastritis than to DLBCL. Patients with higher number of tumor infiltrating FOXP3+ cells at study entry seem to have better response to antibiotics. Kinetics of Treg and tumor cells are influenced by type of treatment.
35 citations
TL;DR: The content of regulatory T-cells was positively and the content of follicular helper T- cells inversely correlated with a higher stage of the disease at diagnosis, implying that the microenvironment changes during tumor dissemination.
34 citations
TL;DR: Immune cell infiltration is common to many tumors and has been recognized by pathologists for more than 100 years and expression of PD-L1, by 50% or more tumor cells, identified NSCLC patients with double the response rate to anti-PD-1.
33 citations
TL;DR: The translocation t(14;18) is present in approximately 90% of FL leading to the upregulation of the anti-apoptotic protein BCL2, that may constitute a promising molecular target for therapeutic approaches.
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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