M2 Macrophage Infiltration Is Closely Associated with Poor Prognosis for Adult T-Cell Leukemia/Lymphoma (ATLL),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3672-3672 ◽  
Author(s):  
Daisuke Niino ◽  
Yoshihiro Komohara ◽  
Yoshizo Kimura ◽  
Masanori Takeuchi ◽  
Hiroaki Miyoshi ◽  
...  
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Poor Prognosis ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Adult T Cell Leukemia ◽  
Cd163 Expression ◽  
Tumor Area

Abstract Abstract 3672 Background: Adult T-cell leukemia/lymphoma (ATLL) is a peripheral T-cell lymphoma caused by a retrovirus, human T-cell lymphotropic virus type I, and characterized by an aggressive clinical course and poor prognosis. Although several factors associated with this poor prognosis have been identified, including high-level Ki67 antigen expression and high serum levels of calcium, parathyroid hormone-related protein, soluble interleukin-2 receptor, β2-microglobulin, and neuron-specific enolase, the accuracy of current prognostic models for prediction of the outcome of treatment is inadequate, and clinically relevant biomarkers have not been established. Tumor-associated macrophages, which are known to possess the immunosuppressive M2 macrophage phenotype, contribute to tumor growth, invasion, and metastasis by producing various mediators. Macrophage polarization is divided into types M1 and M2 based on the expression of membrane receptors, cytokines, and chemokines. M1 expresses CD80, interleukin (IL)-6, IL-12, and chemokine receptor 7, while M2 expresses CD163, IL10, and chemokine ligand 22. The classically activated M1 macrophages exhibit antitumor functions and the alternatively activated M2 macrophages protumor functions, which contribute to the development and progression of tumors. CD163 is a monocyte/macrophage-restricted membrane protein belonging to the scavenger receptor cysteine-rich domain family and it functions as an endocytic receptor for a hemoglobin-haptoglobin complex. CD163 expression has been associated with an anti-inflammatory M2 macrophage phenotype and is believed to be useful for distinguishing M2 macrophages from pro-inflammatory M1 macrophages. Macrophages, especially M2 polarized macrophages, preferentially express CD163, but no studies have investigated macrophage phenotypes in ATLL. The aim of our study was therefore to investigate CD163 expression, which has been used as a marker for M2 macrophages, and the relationship between macrophage activation and prognosis for ATLL in order to gain new information about the therapeutic implications of this relationship for ATLL. Methods: Between 1985 and 2003, 75 cases of ATLL were examined. The male-to-female ratio was 1.34:1 and the median age 63 years (range: 35–87 years). Advanced clinical stages were identified in 75% of the patients, and lactic dehydrogenase was elevated in 25%. Most patients were treated with combination chemotherapy and the median survival period was 271 days (range: 4–3, 807 days). We performed a retrospective study on the immunohistochemical expression of macrophage markers (CD68, CD163) and their correlation with overall survival for the 75 ATLL patients. Paraffin sections were examined immunohistochemically by using anti-CD68 (PGM1) and anti-CD163 antibodies, and the absolute number of intratumoral macrophages in the ATLL specimens was determined. Kaplan-Meier survival estimates were subjected to comparative univariate analyses using the log-rank test. Cox proportional-hazard regression test was used for the multivariate analysis. P-values of less than 0.05 were considered significant. Results: The number of CD68-positive macrophages in ATLL tissues did not correlate with overall survival (P =0.25), whereas patients with a large number of CD163-positive macrophages (>250 cells/mm2 tumor area; n=37) had worse outcomes than those with a small number (<250 cells/mm2 tumor area; n=36) (P =0.05). Meanwhile, a higher ratio of CD163-positive to CD68-positive macrophages in ATLL significantly correlated with worse overall survival (P =0.039). Multivariate analysis confirmed that high CD163/CD68 ratio was an independent prognostic factor. Conclusions: Considering that high CD163/CD68 ratio reflects the proportion of macrophages polarized to the M2 phenotype, our findings further indicate that activation of macrophages towards the M2 phenotype correlates with worse prognosis. They also suggest that immunohistochemical analysis of M2 macrophages at the time of diagnosis can provide additional relevant prognostic information. However, these findings need to be further explored in future studies. Disclosures: No relevant conflicts of interest to declare.

Spatial analysis of tumor immune microenvironment (TIME) in patients treated with Bintrafusp alfa.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3070-3070
Author(s):  
Houssein Abdul Sater ◽  
Jeffrey Robinson ◽  
Julius Strauss ◽  
Margaret Elena Gatti-Mays ◽  
Jason Redman ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Cell ◽  
Nk Cell ◽  
Cd8 T Cell ◽  
Tumor Control ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Linear Discriminant ◽  
Number Of Patients

3070 Background: Bintrafusp alfa is a first-in-class bifunctional fusion protein composed of the extracellular domain of TGF-βRII receptor (TGF-β “trap”) fused to a human IgG1 mAb blocking PD-L1. In preclinical models, bintrafusp alfa treatment promoted CD8+ T cell and NK cell activation, and both immune cell (IC) populations were required for optimal bintrafusp alfa mediated tumor control. However, the effect of bintrafusp alfa on TIME in humans has not been reported. Methods: In this unplanned interim analysis of a biomarker expansion cohort (NCT 02517398), patients (pts) with advanced non-small cell lung cancer (NSCLC) underwent paired biopsies (bx) before and on treatment with bintrafusp alfa (~ 50 days apart). The objective was to evaluate frequency and localization of tumor infiltrated ICs by IHC. Out of 12 pts, 7 had matched (Pre vs Post) tumor-containing specimens sufficient for multiplex immunofluorescence (MxIF) analysis of TIME. Four pts were excluded as Post bx histology for 3/12 [2 PR (partial response), 1 SD (stable disease)] was negative for tumor (necrosis or fibrosis) and 1/12 did not have a Post bx performed. Results: TIME study shows CD8 T cell infiltrates were increased in Post compared to Pre bx (median 161 vs 62/mm²; interquartile range [IQR] 65–396/mm² vs 31–135/mm²; p = 0·04). While M2 macrophages were also increased (median 800 vs 367/mm²; IQR 776–1131/mm² vs 171–831/mm²; p = 0·04), the ratio of M1/M2 was reversed in pts with SD (↑) compared to pts with PD (↓). Other ICs such as CD4, T-regs, NK cells and M1 macrophages were not changed. On average compared to baseline, M2 macrophages were > 2 fold closer to every other IC in pts with PD, but > 2 fold further from any IC in pts with SD. Tregs were relatively closer to other IC in PD pts. Linear Discriminant Analysis was also performed and results indicate that differential IC densities (mainly M1 macrophages and CD4 T cells) do perform as classifiers between long ( > 5 months) and short ( < 5 months) term responses. Conclusions: This study suggests that bintrafusp alfa not only can enhance intratumoral effector IC infiltrates (CD8) but also has a modulating effect on the spatial distribution of both M1/M2 macrophages within the NSCLC TIME. The differential proximity of M2 macrophages to other IC infiltrates and changes in M1/M2 ratios in association with response suggests that an M1/M2 macrophage balance is directly involved in response and/or resistance to bintrafusp alfa. Given the limited number of patients in this cohort, we intend to study effects of bintrafusp alfa in a larger cohort of patients. Clinical trial information: 02517398 .

A case of vesiculobullous adult T‐cell leukemia/lymphoma with a poor prognosis

2021 ◽  
Vol 48 (4) ◽  
Author(s):  
Takuya Kawamura ◽  
Shinya Kitamura ◽  
Yosuke Mai ◽  
Tatsuro Sugai ◽  
Shota Takashima ◽  
...  
Keyword(s):  
T Cell ◽  
Poor Prognosis ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

scholarly journals Acid Sphingomyelinase Controls Early Phases of Skeletal Muscle Regeneration by Shaping the Macrophage Phenotype

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3028
Author(s):  
Paulina Roux-Biejat ◽  
Marco Coazzoli ◽  
Pasquale Marrazzo ◽  
Silvia Zecchini ◽  
Ilaria Di Renzo ◽  
...  
Keyword(s):  
Skeletal Muscle ◽  
Satellite Cells ◽  
Muscle Regeneration ◽  
Acid Sphingomyelinase ◽  
Skeletal Muscle Regeneration ◽  
Sphingolipid Metabolism ◽  
M2 Macrophages ◽  
Macrophage Phenotype ◽  
M1 Macrophages ◽  
Early Phases

Skeletal muscle regeneration is a complex process involving crosstalk between immune cells and myogenic precursor cells, i.e., satellite cells. In this scenario, macrophage recruitment in damaged muscles is a mandatory step for tissue repair since pro-inflammatory M1 macrophages promote the activation of satellite cells, stimulating their proliferation and then, after switching into anti-inflammatory M2 macrophages, they prompt satellite cells’ differentiation into myotubes and resolve inflammation. Here, we show that acid sphingomyelinase (ASMase), a key enzyme in sphingolipid metabolism, is activated after skeletal muscle injury induced in vivo by the injection of cardiotoxin. ASMase ablation shortens the early phases of skeletal muscle regeneration without affecting satellite cell behavior. Of interest, ASMase regulates the balance between M1 and M2 macrophages in the injured muscles so that the absence of the enzyme reduces inflammation. The analysis of macrophage populations indicates that these events depend on the altered polarization of M1 macrophages towards an M2 phenotype. Our results unravel a novel role of ASMase in regulating immune response during muscle regeneration/repair and suggest ASMase as a supplemental therapeutic target in conditions of redundant inflammation that impairs muscle recovery.

Abstract 660: Macrophage Specific Deficiency of the Transient Receptor Potential Canonical 3 Channel Reduces Apoptosis and Necrosis in Advanced Atherosclerotic Plaques

2016 ◽  
Vol 36 (suppl_1) ◽  
Author(s):  
Sumeet A Solanki ◽  
Guillermo Vazquez
Keyword(s):  
Bone Marrow ◽  
Transient Receptor Potential ◽  
Receptor Potential ◽  
Atherosclerotic Plaques ◽  
M2 Macrophage ◽  
M2 Macrophages ◽  
M1 Macrophages ◽  
Transient Receptor Potential Canonical ◽  
Transient Receptor ◽  
Apoptosis And Necrosis

Background: Macrophage apoptosis plays a critical role in progression of atherosclerosis. Previous studies suggest that M1 and M2 macrophage phenotypes dominate atherosclerosis. Recently, we showed that advanced lesions in the aortic root of Apoe -/- mice transplanted with bone marrow deficient in the calcium-permeable channel Transient Receptor Potential Canonical 3 (TRPC3) are characterized by reduced areas of necrosis and less apoptotic macrophages. However, the donor mice used in these studies had global deficiency of TRPC3, raising the question whether the observed phenotype was also contributed by TRPC3-deficient non-myeloid cells which could undermine the true impact of macrophage deletion of TRPC3. To address this important question, we generated mice with macrophage-specific loss of TRPC3 function (MacTrpc3 -/- ). Methods & results: 13 six week-old female Ldlr -/- mice were irradiated and transplanted with Ldlr -/- (control) or MacTrpc3 -/- Ldlr -/- (experimental) bone marrow and kept on high fat diet for 14 weeks. At the end of the diet period, aortic roots were sectioned and processed for atherosclerotic lesion analysis. Total lesion size (H&E), neutral lipid (Oil Red O) and macrophage content (CD68 staining) were not different between groups. However, we found a 1.7 fold decrease (P=0.01) in percent necrotic area in advanced lesions of MacTrpc3 -/- Ldlr -/- mice (23.12 ± 2.07%, n=10) compared to controls (39.63 ± 5.93%, n=10). Using in situ TUNEL we found that MacTrpc3 -/- Ldlr -/- lesions have less apoptotic cells compared to controls, and these overlapped with CD68 + areas. Using iNOS and mannose receptor as markers for M1 and M2 macrophages, respectively, we found that both subsets overlapped with CD68 + and TUNEL + positive areas, with no differences between groups (n=5). Previously, we showed that M1, but not M2 macrophages derived from MacTrpc3 -/- mice, had reduced apoptosis. This suggests that reduced plaque necrosis of MacTrpc3 -/- Ldlr -/- mice may be due to reduced apoptosis of M1 macrophages. In sum, these in vivo studies indicate that macrophage-specific deficiency of TRPC3 has a genuine beneficial effect on advanced atherosclerotic plaques, reducing apoptosis and necrosis, probably due to a selective effect of TRPC3 on M1 macrophages.

Clinical Features, Treatment Outcome, and Predictive Biomarkers In Adult T-Cell Leukemia/Lymphoma: University Of Miami Experience

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1340-1340
Author(s):  
Agustin Pimentel ◽  
German Campuzano-Zuluaga ◽  
Luis Diaz ◽  
Jennifer R. Chapman-Fredricks ◽  
Juan Carlos Ramos
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
Categorical Variables ◽  
High Dose ◽  
Nuclear Staining ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Ifna Therapy ◽  
Potential Biomarker

Abstract Introduction Adult T-cell leukemia/lymphoma (ATLL) is a rare aggressive malignancy with a poor prognosis caused by HTLV-1. Miami is proximal to the Caribbean where HTLV-I is endemic, and we encounter a relatively high number of ATLL cases. Herein, we have performed the largest single institution retrospective analysis of ATLL patients (pts) to date in the U.S. We studied ATLL patient characteristics, treatment patterns, and disease outcome. In addition, we investigated the expression of IRF-4/MUM-1 in available specimens. Previously, our group demonstrated an association between lack of IRF-4/MUM-1 and response to AZT-interferon-alpha (AZT/IFNa) therapy in a small ATLL cohort. IRF-4/MUM-1 is a putative NF-kB target gene that encodes a transcription factor. IRF-4/MUM-1 expression has been associated with interferon resistance in preclinical studies, and is a poor prognostic marker in some lymphomas. One of our objectives is evaluate and validate IRF-4/MUM-1 as a potential biomarker for treatment selection and outcome in ATLL. Methods We analyzed 125 pts diagnosed with ATLL in UM/JMH between 1987 and 2013. We evaluated MUM-1 protein expression using immunohistochemistry (IHC) on either tissue sections, or cytospins prepared from CD4+-enriched peripheral blood leukemic specimens using 30% nuclear staining as a cut-off positive value, or by western blot (WB) analysis in some cases where fresh or DMSO preserved ATLL cells were not available. Kaplan-Meier survival curves, log-rank test where used for survival analysis. Mann-Whitney's U test was used to compare non-normally distributed continuous variables. Pearson's chi-squared or Fischer's exact tests were used to compare categorical variables. Results ATLL pts were 45% male and 55% female with a median age of 51 (17-91). The great majority of pts were Afro-Caribbean (82%), followed by U.S. African American (12%) and South American (6%). A total of 109 pts have been analyzed for treatment response so far, including 51 acute, 50 lymphomatous (L), 6 chronic (5 unfavorable), and 2 smoldering types. The median overall survival (OS) for acute and L was 6 and 10 months respectively, and not reached for chronic and smoldering types (figure 1). Fifty-six pts (34 acute, 14 L, 5 unfavorable chronic, 1 chronic, and 2 smoldering) were treated with high-dose AZT/IFNa as first line therapy. The complete and overall response rates (CR and ORR) after AZT/IFNa for acute/unfavorable chronic (A/UC) vs. L types were 25% vs. 0.7%, and 54% vs. 21% respectively. Seventy-seven pts received chemotherapy at some point during their treatment. The CR rate and ORR for A/UC vs. L-type pts treated with chemotherapy-based regimens were 40 % vs. 21%, and 70% vs. 77% respectively. However, we observed a significantly longer median progression-free survival (PFS) and sustained responses in pts with A/UC ATLL who achieved a CR with AZT/IFNa (168.1 wks), as compared to chemotherapy (61.1 wks), which translated into an overall survival benefit. Next, in order to determine whether IRF-4/MUM-1 predicted response to AZT/IFNa, 66 ATLL cases were analyzed by IHC and/or WB. The results showed that 38.5% of A/UC were IRF-4/MUM-1+ as compared to 82.1% in the L type (<P.0001). Evaluable pts for AZT/IFNa response demonstrated that 55% of A/UC MUM-1(-) cases had a CR as compared to 0% in MUM-1+ pts (P=.009). In the L group, AZT/IFNa responses were minimal and were mainly limited to stable disease. Subgroup analysis showed that median OS for MUM-1(-) vs. MUM-1+ in A/UC subtype was 38.4 wks vs. 27.6 wks (P=0.275) (figure 2), respectively. In the L subtype, median OS for MUM-1(-) vs. MUM-1+ was 25.7 wks vs. 60.3 wks (P=0.02) (figure 3), respectively. Finally, the median PFS in AZT/IFNa-treated A/UC pts favored the MUM-1(-) as compared to MUM-1+ cases. Conclusion Our data demonstrate that AZT/IFNa therapy is beneficial in leukemic type (A/UC) lacking IRF-4/MUM-1 expression, while L type is generally resistant to this treatment. On the other hand, IRF-4/MUM-1 expression is associated with a favorable outcome in L subtype. We have identified IRF-4/MUM-1 expression as a predictive marker that could be used in deciding upfront therapy (i.e. AZT/IFNa vs. standard chemotherapy) in leukemic ATLL subtypes. Our study findings must be confirmed and validated in a larger ATLL cohort. Disclosures: No relevant conflicts of interest to declare.

Hodgkin Lymphoma-Like Adult T-Cell Leukemia/Lymphoma Shows An Indolent Clinical Course: Analysis Of 7 Cases

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5081-5081
Author(s):  
Daisuke Niino ◽  
Shigeo Nakamura ◽  
Koichi Ohshima
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
Lymph Node ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Clinical Course ◽  
Giant Cells ◽  
Cell Leukemia ◽  
Tissue Samples ◽  
Adult T Cell Leukemia

Abstract Adult T-cell leukemia/lymphoma (ATLL) is a human T-lymphotropic virus type-1 (HTLV-1)-associated T-cell malignancy. The clonality of T-cells with HTLV-I proviral DNA integration changes from undetectable to polyclonal, and then further to monoclonal upon malignant transformation. Analysis of proviral DNA integrated in cellular DNA has shown that leukemic cells are always infected with HTLV-I. These cells are also consistently monoclonal with respect to proviral integration, which indicates that they originated from a single cell infected with HTLV-I. On the basis of findings related to changes in peripheral blood, the clinical stage gradually progresses from carrier to smoldering, chronic and acute-type leukemia. In a previous series of studies, we and other groups characterized the histopathological changes in HTLV-I-associated lymph node lesions. In addition to the typical ATLL pleomorphic and anaplastic large cell types, we identified lymph nodes with an unusual Hodgkin disease-like histology (Hodgkin-like ATLL) in HTLV-I-positive patients. Hodgkin-like ATLL showed prodromal clinical features, but the effect of conventional therapy was poor in patients with this type of lymph node lesion and most patients later developed typical ATLL. Recently, new drugs and therapies (stem cell transplantation) for ATLL have been developed, and the prognosis of ATLL has improved. It is now believed that Hodgkin-like ATLL has a relatively better prognosis than typical ATLL. In this study, we investigated the rare Hodgkin-like morphologic variant of ATLL and reexamined its prognosis. Seven cases were retrieved from the archives of the Department of Pathology, Department of Pathology, Kurume University (from 2006 to 2010). Portions of the tissue samples were formalin-fixed, paraffin-embedded, and stained with hematoxylin-eosin (H&E). Two hematopathologists (D.N. and K.O.) reviewed all cases and classified them morphologically on the basis of WHO classification. Paraffin sections from each sample were immunostained with monoclonal antibodies against CD3, CD4, CD8, CD15, CD20, CD30, TIA1, PAX5 and CCR4. Heat-mediated antigen retrieval was performed. All analyses were performed in a single laboratory. EB virus-encoded small RNA (EBER) was detected by in situ hybridization. Other portions of the tissue samples were frozen and used for DNA isolation and gene analysis. The monoclonal or oligoclonal integration of HTLV-1 DNA was examined by digestion with EcoRI, as described previously. In all cases, serum test results were positive for HTLV-1 and proviral HTLV-1 DNA bands were found, although the bands were weaker than those usually seen in typical ATLL. The median age of patients was 60 (range 40-69), with two males and five females. Laboratory data showed an elevation of lactic dehydrogenase (LDH) in six cases. Ann Arbor staging (I/II/III/IV) was 1/0/1/5 patients. Six patients received chemotherapy, one received chemotherapy with stem cell transplantation. Two patients died within 13 and 21 months, whereas five are still alive. The median survival was 31 months (range 13 to 58 months). The five-year overall survival is 71.4%. Histologically, the lymph nodes exhibited a relatively preserved nodal architecture with diffuse infiltration of small-sized lymphocytes. Small aggregated foci or clusters of a few giant cells with irregularly lobulated nuclei were scattered throughout the expanded paracortex. In the immunohistological analysis, the giant cells were positive for CD30, CD15, and PAX5 but negative for CD20, CD3, TIA-1 and CCR4. The proliferating small lymphocytes were mainly positive for CD3, CD4 and CCR4 but negative for CD8 in all cases. All patients were positive for EBER in the nuclei of the giant cells. The clinical outcome for patients with typical ATLL is generally poor with a median survival time of less than three years. However, patients with Hodgkin-like ATLL showed an indolent clinical course and relatively good survival with 71.4% five-year overall survival. Our findings indicate that pathologists and hematologists in HTLV-1 endemic areas should be more aware of ATLL and understand this morphologic variant. Disclosures: No relevant conflicts of interest to declare.

Recent Significance of Allogeneic Hematopoietic Stem Cell Transplantation for Adult T Cell Leukemia/Lymphoma (ATL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1241-1241
Author(s):  
Masahito Tokunaga ◽  
Nobuaki Nakano ◽  
Ayumu Kubota ◽  
Mayumi Tokunaga ◽  
Takahiro Itoyama ◽  
...  
Keyword(s):  
Overall Survival ◽  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Clinical Stage ◽  
Overall Survival Rate ◽  
Hematopoietic Stem ◽  
Adult T Cell Leukemia ◽  
Lymphoma Type

Abstract Introduction: Adult T cell leukemia/lymphoma (ATL) is a poor prognostic T-cell malignancy and the median survival time of aggressive type ATL is about a year regardless of intensive chemotherapy. Since 2001, several studies mainly from Japan show that allogeneic hematopoietic stem cell transplantation (allo-HSCT) has improved overall survival (OS) of ATL. To confirm the survival of the ATL patients received treatment such as chemotherapy and allo-HSCT and the usefulness of allo-HSCT on ATL, we analyzed retrospectively the patients with ATL treated recently in our institute. Patients and methods: There were total 198 patients who were consecutively hospitalized and received treatments as ATL between July, 2006 and December, 2013 in Imamura Bun-in Hospital that located at Kagoshima, an endemic area of HTLV-1 infection in Japan. This time we studied about backgrounds (age, gender, subtypes of ATL, performance status (PS) at diagnosis and clinical stage) of the patients, content of allo-HSCT, prognostic index for acute and lymphoma type ATL (ATL-PI) and survival duration from diagnosis retrospectively. The comparisons between the mean values were performed by Student’s t test or the Mann–Whitney test. The overall survival from diagnosis (OS) was analyzed with Kaplan-Meir method and Cox regression analysis about OS was performed. Statistical significance defined P<0.05. Statistical analysis ware performed with STATA Version 12 software (Stata Corp). Results: Median age of the patients was 62.5 (range: 32.5-90.5) years old and they were 104 male and 94 female. One hundred forty four patients were initially diagnosed as acute type ATL, 26 as lymphoma type, 18 as chronic type and 10 as smoldering type respectively. ECOG PS at diagnosis was score 0 to 1 in 155 patients (78.3 %) and score 2 to 4 in 43 patients (21.7 %). Clinical stage at diagnosis was stage I to II in 12 patients (6 %) and stage III, IV in others (94 %). Eventually 68 patients received allo-HSCT (allo-bone marrow transplantation in 48, allo-peripheral blood stem cell transplantation in 5 and cord blood transplantation in 15 patients) and all of them were acute and lymphoma type. Fifty-three patients received stem cell from unrelated donors. The median study observation period was 293.5 (range: 7-2539) days. In all 198 patients OS rate at 1 and 3 year were 41.9 % and 17.9 % respectively and 50% OS was 9.8 months and the results were comparable to the past reports. Overall survival rate at 1- and 3-year of the patients who were able to be received allo-HSCT was 54.8 % and 36.5 %, and 50% OS of them was 16.2 months. Overall survival rate at 1- and 3-year of the patients who were not received allo-HSCT and mainly received chemotherapies such as CHOP or VCAP-AMP-VECP regimens was 35.0 % and 7.3 %, and 50% OS was 8.2 months. ATL-PI was reported as a new prognostic prediction tool for patients with acute and lymphoma type ATL, and had prognostic power in acute and lymphoma type ATL who were not received allo-BMT in the present study (1 year OS : 57.2 %, 34.6 % and 18.8 % at low, intermediate and high risk respectively, p<0.000). In the patients received allo-HSCT, there were no patients with high risk of ATL-PI and the patients with low risk were liable to have worse OS than the patients with intermediate risk (1 year OS : 50.4 %, 62.2 % and 3 year OS : 25.7 %, 56.6 % at low and intermediate risk respectively, p=0.114). Conclusions: This retrospective analysis estimates that outcome of chemotherapies for ATL patients were not so improved and allo-HSCT has promising strategy for the patients with ATL who has indication for that. But we reveal that some of patients with low risk of ATL-PI received allo-BMT have poor outcome, these findings should be confirmed in a prospective study. Disclosures No relevant conflicts of interest to declare.

The T Cell Receptor (TCR) Repertoire Is a Key Determinant of the Tumour Microenvironment (TME) in Diffuse Large B Cell Lymphoma (DLBCL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3893-3893
Author(s):  
Colm Keane ◽  
Kimberly Jones ◽  
Clare Gould ◽  
David Hamm ◽  
Peter Wood ◽  
...  
Keyword(s):  
Immune Response ◽  
Overall Survival ◽  
T Cells ◽  
T Cell ◽  
De Novo ◽  
T Cell Response ◽  
M2 Macrophages ◽  
Tcr Repertoire ◽  
Immune Score ◽  
The Relationship

Abstract Background: We have recently demonstrated that an 'immune score' is strongly and independently prognostic in de novo DLBCL treated with R-CHOP immuno-chemotherapy. The score quantifies the relative composition of immune effectors (T cells) and checkpoints (e.g. PD-1 axis molecules and M2 macrophages), as a measure of net anti-tumoral immunity within the TME. It is also known that a diverse TCR repertoire is a hallmark of a robust anti-HIV T cell immune response; conversely in metastatic melanoma treated with anti-PD-1 checkpoint blockade, narrow more clonal TCR repertoires are associated with favorable response. The relationship between the intra-tumoral TCR repertoire and the TME in DLBCL following R-CHOP immuno-chemotherapy is unknown. Methods High-throughput unbiased TCR β chain sequencing was performed on 116 nodal tissues (101 de novo DLBCL patients treated with R-CHOP with long-term follow-up including 8 EBV+DLBCL; and 15 age/gender matched healthy lymph nodes). Outcomes included measurement of productive uniques (a measure of the number of functional T cells with a distinct TCR rearrangement or 'richness'); entropy (a measure of TCR 'diversity'), 'clonality' (a measure of clonal expansions) and the 'maximal frequency' of the most highly expressed clone within tumor biopsies. Results were compared to digital quantification (by nanoString) of key immune effector and checkpoint genes within the TME, the immune score, malignant cell-of-origin (COO), R-IPI and patient survival. Results: First we compared the TCR repertoire in lymphomatous and healthy nodes. There was a marked increase in clonality, reduced diversity and high maximal frequency within DLBCL nodes relative to healthy nodal tissue (both p<0.0001), consistent with an abnormally narrow TCR repertoire of antigen-specific T cells. Next, we tested the relationship between TCR and the TME. Notably, there was modest (r=0.3-0.7) but highly significant (all p<0.001) positive correlations between both richness and diversity (but not clonality) with CD3/CD4/CD8 T cells, and a range of immune checkpoints including PD-L1, PD-L2, LAG-3, CSF-1 and TIM-3. These findings are strongly suggestive of an adaptive immune response, in which malignant B cells influence (i.e. 'adapt') the TME in an attempt to counter an effective anti-lymphoma T-cell response that is in part influenced by the breadth of the TCR repertoire. Then we investigated the TCR repertoire in the context of prognosis and overall survival (OS) following R-CHOP. There were no correlations between COO or R-IPI with any TCR parameter. However, the presence of a high maximal frequency in the tumour biopsy was associated with significantly inferior 5 year OS of 59% compared to 81% in patients without a high maximal frequency (p=0.03, Figure 1). As expected, the immune score stratified patients into highly disparate outcomes: high-score 5-year overall survival 96% versus 42% for low-score (p<0.0001). Interestingly, there were significant differences in the TCR repertoire between the two groups. There was a significant increase for both richness and diversity in high immune score lymphoma patients (p=0.015 and p=0.018 respectively). In keeping, clonality was not increased in high-immune score patients. The only samples associated with increased T cell clonality were those patients with very high levels of intratumoral EBV, potentially reflecting the latent viral antigens expressed by this lymphoma. In the group of patients with poor prognosis (5 year OS 59%), defined by high maximal frequency, the immune score stratified two groups with very different outcomes (5 year OS 90% vs. 30%, p=0.003). Conclusions: These findings indicate the TCR repertoire as a key parameter of the TME that the malignant B cell attempts to narrow. A broad TCR repertoire is associated with a good prognostic immune score (i.e. increased T cells relative to PD-1 axis molecules and M2 macrophages checkpoints) after R-CHOP immunoÐchemotherapy, whereas a more clonal T cell response is associated with significantly inferior outcome. Figure 1. Figure 1. Disclosures Hamm: Adaptive Biotech: Employment.

scholarly journals Soluble CD30 is a new biomarker to predict two-year overall survival of adult T cell leukemia/lymphoma patients

Retrovirology ◽  
2014 ◽  
Vol 11 (Suppl 1) ◽  
pp. P2 ◽  
Author(s):  
Ratiorn Pornkuna ◽  
Shigeki Takemoto ◽  
Michihiro Hidaka ◽  
Yoshio Haga
Keyword(s):  
Overall Survival ◽  
T Cell ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Soluble Cd30
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