The tumor microenvironment (TME) and limited immune surveillance
play important roles in lymphoma pathogenesis. Here we
aimed to characterize immunological profiles of diffuse large B-cell
lymphoma ...(DLBCL) and predict the outcome in response to
immunochemotherapy. We profiled the expression of 730 immune-related
genes in tumor tissues of 81 patients with DLBCL utilizing the Nanostring
platform, and used multiplex immunohistochemistry to characterize T-cell
phenotypes, including cytotoxic T cells (CD8, Granzyme B, OX40, Ki67),
T-cell immune checkpoint (CD3, CD4, CD8, PD1, TIM3, LAG3), as well as
regulatory T-cells and Th1 effector cells (CD3, CD4, FOXP3, TBET) in 188
patients. We observed a high degree of heterogeneity at the transcriptome
level. Correlation matrix analysis identified gene expression signatures
with highly correlating genes, the main cluster containing genes for cytolytic
factors, immune checkpoint molecules, T cells and macrophages, together
named a TME immune cell signature. Immunophenotyping of the distinct
cell subsets revealed that a high proportion of immune checkpoint positive
T cells translated to unfavorable survival. Together, our results demonstrate
that the immunological profile of DLBCL TME is heterogeneous and clinically
meaningful. This highlights the potential impact of T-cell immune
checkpoint in regulating survival and resistance to immunochemotherapy.
(Registered at clinicaltrials.gov identifiers: NCT01502982 and NCT01325194.)
Summary
Follicular lymphoma (FL) constitutes a significant proportion of lymphomas and shows frequent relapses. Beyond conventional chemotherapy, new therapeutic approaches have emerged, focussing on ...the interplay between lymphoma cells and the microenvironment. Here we report the immunophenotypic investigation of the microenvironment of a clinically well‐characterized prospective cohort (study SAKK35/10, NCT01307605) of 154 treatment‐naïve FL patients in need of therapy, who have been treated with rituximab only or a combination of rituximab and the immunomodulatory drug lenalidomide/Revlimid® A high ratio of CD4‐ to CD8‐positive T cells (P = 0·009) and increased amounts of PD1+ tumour‐infiltrating T cells (P = 0·007) were associated with inferior progression‐free survival in the whole cohort. Interestingly, the prognostic impact of PD1+ T cells and the CD4/CD8 ratio lost its significance in the subgroup treated with R2. In the latter group, high amounts of GATA3+ T helper (Th2) equivalents were associated with better progression‐free survival (P < 0·001). We identified tumour microenvironmental features that allow prognostic stratification with respect to immuno‐ and combined immuno‐ and immunomodulatory therapy. Our analysis indicates that lenalidomide may compensate the adverse prognostic implication of higher amounts of CD4+ and, particularly, PD1+ T cells and that it has favourable effects mainly in cases with higher amounts of Th2 equivalents.
Correction added on 11 February 2020, after online publication: The NCT‐trial number was previously incorrect and has been updated in this version.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
The inflammatory response triggered by stroke has been viewed as harmful, focusing on the influx and migration of blood-borne leukocytes, neutrophils, and macrophages. This review hypothesizes that ...the brain and meninges have their own resident cells that are capable of fast host response, which are well known to mediate immediate reactions such as anaphylaxis, known as mast cells (MCs). We discuss novel research suggesting that by acting rapidly on the cerebral vessels, this cell type has a potentially deleterious role in the very early phase of acute cerebral ischemia and hemorrhage. Mast cells should be recognized as a potent inflammatory cell that, already at the outset of ischemia, is resident within the cerebral microvasculature. By releasing their cytoplasmic granules, which contain a host of vasoactive mediators such as tumor necrosis factor-α, histamine, heparin, and proteases, MCs act on the basal membrane, thus promoting blood–brain barrier (BBB) damage, brain edema, prolonged extravasation, and hemorrhage. This makes them a candidate for a new pharmacological target in attempts to even out the inflammatory responses of the neurovascular unit, and to stabilize the BBB after acute stroke.
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NUK, OILJ, SAZU, UKNU, UL, UM, UPUK
Primary testicular lymphoma is a rare and aggressive lymphoid malignancy, most often representing diffuse large B-cell lymphoma histologically. Tumor-associated macrophages and tumor-infiltrating ...lymphocytes have been associated with survival in diffuse large B-cell lymphoma, but their prognostic impact in primary testicular lymphoma is unknown. Here, we aimed to identify macrophages, their immunophenotypes and association with lymphocytes, and translate the findings into survival of patients with primary testicular lymphoma. We collected clinical data and tumor tissue from 74 primary testicular lymphoma patients, and used multiplex immunohistochemistry and digital image analysis to examine macrophage markers (CD68, CD163, and c-Maf), T-cell markers (CD3, CD4, and CD8), B-cell marker (CD20), and three checkpoint molecules (PD-L1, PD-L2, and PD-1). We demonstrate that a large proportion of macrophages (median 41%, range 0.08-99%) and lymphoma cells (median 34%, range 0.1-100%) express PD-L1. The quantity of PD-L1
CD68
macrophages correlates positively with the amount of PD-1
lymphocytes, and a high proportion of either PD-L1
CD68
macrophages or PD-1
CD4
and PD-1
CD8
T cells translates into favorable survival. In contrast, the number of PD-L1
lymphoma cells or PD-L1
macrophages do not associate with outcome. In multivariate analyses with IPI, PD-L1
CD68
macrophage and PD-1
lymphocyte contents remain as independent prognostic factors for survival. In conclusion, high PD-L1
CD68
macrophage and PD-1
lymphocyte contents predict favorable survival in patients with primary testicular lymphoma. The findings implicate that the tumor microenvironment and PD-1 - PD-L1 pathway have a significant role in regulating treatment outcome. They also bring new insights to the targeted thera py of primary testicular lymphoma.
Purpose: Tumor-associated macrophage (TAM) content predicts survival in follicular lymphoma (FL) patients treated with chemotherapy.
The aim of this study was to determine how combination of ...rituximab with chemotherapy influences TAM-associated clinical outcome.
Experimental Design: Expression of a macrophage marker, CD68, was determined immunohistochemically from FL samples of 96 patients treated with
rituximab and cyclophosphamide-Adriamycin-vincristine-prednisone regimen. Of them, 71 received therapy at diagnosis and 25
at relapse. Neutrophil and CD3+ lymphocyte counts were also measured. The median follow-up time for the cohort was 54 months.
Fourty-five patients previously treated with chemotherapy served as a control group.
Results: Consistent with previous studies, high TAM amount was associated with adverse outcome in chemotherapy-treated patients ( P = 0.026). In contrast, after rituximab and cyclophosphamide-doxorubicin-vincristine-prednisone regimen, high TAM content
correlated with longer survival rates. According to Kaplan Meier estimates, the median progression free survival (PFS) was
not reached for patients with high TAM content compared with 45 months for patients with low TAM scores ( P = 0.006). A trend toward a better overall survival (OS) at 5 years was also observed for patients with high TAM content (OS,
97% versus 90%, P = 0.116). The positive prognostic value of TAMs was seen both for the patients treated at diagnosis and at relapse. In multivariate
analyses, TAM content remained an independent prognostic factor for OS and PFS. Neutrophil and CD3+ lymphocyte counts did
not correlate with outcome.
Conclusions: The data suggest that high TAM score is associated with a favorable prognosis in FL patients treated with immunochemotherapy.
Summary
Mantle cell lymphoma (MCL) is a heterogenic non‐Hodgkin lymphoma entity, with a median survival of about 5 years. In 2008 we reported the early – based on the median observation time of ...4 years – results of the Nordic Lymphoma Group MCL2 study of frontline intensive induction immunochemotherapy and autologous stem cell transplantation (ASCT), with more than 60% event‐free survival at 5 years, and no subsequent relapses reported. Here we present an update after a median observation time of 6·5 years. The overall results are still excellent, with median overall survival and response duration longer than 10 years, and a median event‐free survival of 7·4 years. However, six patients have now progressed later than 5 years after end of treatment. The international MCL Prognostic Index (MIPI) and Ki‐67‐expression were the only independent prognostic factors. Subdivided by the MIPI‐Biological Index (MIPI + Ki‐67, MIPI‐B), more than 70% of patients with low‐intermediate MIPI‐B were alive at 10 years, but only 23% of the patients with high MIPI‐B. These results, although highly encouraging regarding the majority of the patients, underline the need of a risk‐adapted treatment strategy for MCL. The study was registered at www.isrctn.org as ISRCTN 87866680.
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BFBNIB, FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SBCE, SBMB, UL, UM, UPUK
Objectives
Testicular diffuse large B‐cell lymphoma (T‐DLBCL) is a rare and aggressive extranodal lymphoma. We have previously shown that high content of tumor‐infiltrating lymphocytes (TILs) and ...PD‐1 expressing TILs associate with better survival in T‐DLBCL. In this study, we have further characterized distinct TIL subtypes and their proportions in association with patient demographics and survival.
Methods
We used multiplex immunohistochemistry to characterize TIL phenotypes, including cytotoxic T‐cells (CTLs; CD8+, OX40+, Granzyme B+, Ki‐67+, LAG‐3+, TIM‐3+, PD‐1+), CD4+ T‐cells (CD3+, CD4+, TIM‐3+, LAG‐3+), regulatory T‐cells (Tregs; CD3+, CD4+, FoxP3+), and T helper 1 cells (Th1; CD3+, CD4+, T‐bet+) in 79 T‐DLBCLs, and correlated the findings with patient demographics and outcome.
Results
We observed a substantial variation in TIL phenotypes between the patients. The most prominent CD8+ TILs were Ki‐67+ and TIM‐3+ CTLs, whereas the most prominent CD4+ TILs were FoxP3+ Tregs. Despite the overall favorable prognostic impact of high TIL content, we found a subpopulation of T‐bet+FoxP3+ Tregs that had a significant adverse impact on survival. Lower content of CTLs with activated or exhausted phenotypes correlated with aggressive clinical features.
Conclusions
Our results demonstrate significant variation in TIL phenotypes and emphasize the adverse prognostic impact of Tregs in T‐DLBCL.
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BFBNIB, DOBA, FZAB, GIS, IJS, IZUM, KILJ, NLZOH, NUK, OILJ, PILJ, PNG, SAZU, SBCE, SBMB, SIK, UILJ, UKNU, UL, UM, UPUK
Primary testicular lymphoma is a rare lymphoid malignancy, most often, histologically, representing diffuse large B-cell lymphoma. The tumor microenvironment and limited immune surveillance have a ...major impact on diffuse large B-cell lymphoma pathogenesis and survival, but the impact on primary testicular lymphoma is unknown. Here, the purpose of the study was to characterize the tumor microenvironment in primary testicular lymphoma, and associate the findings with outcome. We profiled the expression of 730 immune response genes in 60 primary testicular lymphomas utilizing the Nanostring platform, and used multiplex immunohistochemistry to characterize the immune cell phenotypes in the tumor tissue. We identified a gene signature enriched for T-lymphocyte markers differentially expressed between the patients. Low expression of the signature predicted poor outcome independently of the International Prognostic Index (progression-free survival: HR=2.810, 95%CI: 1.228-6.431,
=0.014; overall survival: HR=3.267, 95%CI: 1.406-7.590,
=0.006). The T-lymphocyte signature was associated with outcome also in an independent diffuse large B-cell lymphoma cohort (n=96). Multiplex immunohistochemistry revealed that poor survival of primary testicular lymphoma patients correlated with low percentage of CD3
CD4
and CD3
CD8
tumor-infiltrating lymphocytes (
<0.001). Importantly, patients with a high T-cell inflamed tumor microenvironment had a better response to rituximab-based immunochemotherapy, as compared to other patients. Furthermore, loss of membrane-associated human-leukocyte antigen complexes was frequent and correlated with low T-cell infiltration. Our results demonstrate that a T-cell inflamed tumor microenvironment associates with favorable survival in primary testicular lymphoma. This further highlights the importance of immune escape as a mechanism of treatment failure.
Tumor-infiltrating immune cells have prognostic significance and are attractive therapeutic targets. Yet, the clinical significance of their spatial organization and phenotype in diffuse large B-cell ...lymphoma (DLBCL) is unclear.
We characterized T cells, macrophages, and their spatial interactions by multiplex IHC (mIHC) in 178 patients with DLBCL and correlated the data with patient demographics and survival. We validated the findings on gene expression data from two external DLBCL cohorts comprising 633 patients.
Macrophage and T-cell contents divided the samples into T cell-inflamed (60%) and noninflamed (40%) subgroups. The T cell-inflamed lymphoma microenvironment (LME) was also rich in other immune cells, defining immune hot phenotype, which did not as such correlate with outcome. However, when we divided the patients according to T-cell and macrophage contents, LME characterized by high T-cell/low macrophage content or a corresponding gene signature was associated with superior survival 5-year overall survival (OS): 92.3% vs. 74.4%, P = 0.036; 5-year progression-free survival (PFS): 92.6% vs. 69.8%, P = 0.012. High proportion of PD-L1- and TIM3-expressing CD163- macrophages in the T cell-inflamed LME defined a group of patients with poor outcome OS: HR = 3.22, 95% confidence interval (CI), 1.63-6.37, Padj = 0.011; PFS: HR = 2.76, 95% CI, 1.44-5.28, Padj = 0.016. Furthermore, PD-L1 and PD-1 were enriched on macrophages interacting with T cells.
Our data demonstrate that the interplay between macrophages and T cells in the DLBCL LME is immune checkpoint dependent and clinically meaningful.
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