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: Steps to further decrease the morbidity and mortality of the RIC HSCT and in particular to reduce the incidence of chronic extensive graft-versus-host disease (GVHD) while maintaining tumor control remain the major focus.
42 citations
VU University Medical Center1, Harvard University2, University of London3, University of Würzburg4, Ludwig Maximilian University of Munich5, Paris 12 Val de Marne University6, Claude Bernard University Lyon 17, Saarland University8, St James's University Hospital9, University of British Columbia10, Stanford University11, Karolinska Institutet12, Karolinska University Hospital13
TL;DR: This Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone while refuting the prognostic impact of various other markers.
Abstract: In follicular lymphoma, studies addressing the prognostic value of microenvironment-related immunohistochemical markers and tumor cell-related genetic markers have yielded conflicting results, precluding implementation in practice. Therefore, the Lunenburg Lymphoma Biomarker Consortium performed a validation study evaluating published markers. To maximize sensitivity, an end of spectrum design was applied for 122 uniformly immunochemotherapy-treated follicular lymphoma patients retrieved from international trials and registries. The criteria were: early failure, progression or lymphoma-related death 5 years. Immunohistochemical staining for T cells and macrophages was performed on tissue microarrays from initial biopsies and scored with a validated computer-assisted protocol. Shallow whole-genome and deep targeted sequencing was performed on the same samples. The 96/122 cases with complete molecular and immunohistochemical data were included in the analysis. EZH2 wild-type (P=0.006), gain of chromosome 18 (P=0.002), low percentages of CD8+ cells (P=0.011) and CD163+ areas (P=0.038) were associated with early failure. No significant differences in other markers were observed, thereby refuting previous claims of their prognostic significance. Using an optimized study design, this Lunenburg Lymphoma Biomarker Consortium study substantiates wild-type EZH2 status, gain of chromosome 18, low percentages of CD8+ cells and CD163+ area as predictors of early failure to immunochemotherapy in follicular lymphoma treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP [-like]), while refuting the prognostic impact of various other markers.
42 citations
TL;DR: The interaction between the malignant and non-malignant cells is bidirectional and resembles, at least in part, the pattern seen between non-neoplastic lymphoid cells and the normal microenvironment of lymphoid organs.
38 citations
TL;DR: The results confirm that the correlation between FcγR polymorphisms and clinical outcome is specific to immunotherapy such as rituximab and idiotype vaccination, and not due to any effect on the underlying clinical behavior of the disease or chemotherapy response.
Abstract: Recently, immunoglobulin G Fc receptor (FcγR) polymorphisms have been found to correlate with the clinical response to rituximab or idiotype vaccine in patients with follicular lymphoma Two critical questions are whether the FcγR polymorphisms correlate with the clinical outcomes after chemotherapy alone in patients with follicular lymphoma and whether they can be explained by linking to underlying biology of follicular lymphoma This is an important issue because the clinical decisions about the use of antibody therapy may be based on the FcγR polymorphisms of these patients Here, we analyzed the FcγRIIIa 158 V/F, FcγRIIa 131 H/R, and FcγRIIb 232 I/T polymorphisms in a group of 188 patients with follicular lymphoma who were treated with chemotherapy without rituximab initially In the current study, FcγR polymorphisms neither correlated with response rate or time to progression after induction chemotherapy, nor with time to the initial therapy or overall survival after diagnosis Our results confirm that the correlation between FcγR polymorphisms and clinical outcome is specific to immunotherapy such as rituximab and idiotype vaccination, and not due to any effect on the underlying clinical behavior of the disease or chemotherapy response
37 citations
Cites background from "Impact of the tumor microenvironmen..."
...Several reports have associated tumor-infiltrating immune cells with the clinical outcomes including survival of patients with follicular lymphoma [10,29,30]....
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TL;DR: The use of immune checkpoint inhibitors, including nivolumab and pembrolizumab, in relapsed and refractory patients with lymphoma is proving highly successful and responses in patients with Hodgkin lymphoma appear durable.
Abstract: Purpose of review The purpose of this article is to discuss the tumor microenvironment in lymphoma, and to review potential immune targets that are now becoming relevant because of clinical responses seen with the use of immune checkpoint inhibitors. Recent findings Recent data have shown that cells within the immune microenvironment in lymphoma express programmed death ligand-1 (PD-L1) and many of the intratumoral T cells with an exhausted immune phenotype express programmed cell death-1 (PD-1). This provides a novel opportunity to inhibit the immune checkpoints and initial clinical trials utilizing antibodies that block the interaction between PD-1 and PD-L1 have demonstrated significant clinical responses in various lymphomas, including Hodgkin lymphoma. Summary The use of immune checkpoint inhibitors, including nivolumab and pembrolizumab, in relapsed and refractory patients with lymphoma is proving highly successful. Patients with Hodgkin lymphoma, in particular, have a very high response rate to PD-1 blockade and responses in these patients appear durable.
36 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