CS-1 Is Expressed in Nasal Type NK/T Cell Lymphomas and Angioimmunoblastic T-Cell Lymphomas: Implications for Targeted Therapy with Elotuzumab (HuLuc63).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1779-1779
Author(s):  
Eric D Hsi ◽  
Roxanne Steinle ◽  
Balaji Balasa ◽  
Audie Rice ◽  
Young-Hyeh Ko ◽  
...  
Keyword(s):  
Gene Expression ◽  
Flow Cytometry ◽  
T Cells ◽  
T Cell ◽  
Expression Profiling ◽  
Nasal Type ◽  
T Cell Lymphomas ◽  
Nk T Cells ◽  
Nk T Cell ◽  
Peripheral T Cell Lymphomas

Abstract Background: CS-1 (CRACC, SLAMF7, CD319) is a member of the signaling lymphocyte activating molecule-related receptor family. It is highly and uniformly expressed on the cell surface of benign and malignant plasma cells. We have recently reported the generation of elotuzumab (formerly known as HuLuc63), a humanized antibody targeting CS-1, which is currently in phase 1 trials in relapsed multiple myeloma. Lower levels of CS-1 have also been reported on NK cells and NK-like T-cells (NK/T). CS-1 expression in NK and T-cell lymphomas - aggressive lymphomas for which no effective therapy exists - is unknown. Here, we examined the expression of CS-1 in normal NK/T cells and in a series of NK and peripheral T-cell lymphomas (PTCL). Methods: CS-1 expression in normal NK and T-cells were assessed by gene expression profiling. Flow cytometry (FACSCalibur, Becton Dickinson) was performed on blood from normal samples using a directly conjugated Alexa-488 elotuzumab. Archival formalin-fixed, paraffin-embedded tissues from PTCLs, including angioimmunoblastic T-cell lymphomas (AITL) and nasal type NK/T cell lymphomas were tested for CS-1 expression using the a paraffin-reactive 1G9 monoclonal antibody and automated immunohistochemistry (IHC, Ventana Medical Systems). Results: Gene expression profiling showed CS-1 expression in purified NK and NK/T cells. We confirmed cell surface expression of CS-1 protein on normal blood NK and NK/T cells (n=18 samples) by flow cytometry with Alexa-488-HuLuc63. The majority of normal NK and NK/T cells expressed CS-1 (mean% positive and standard deviation of 96% +/− 4% and 71 % +/− 24%, respectively). We then evaluated tumor samples from patients with nasal type NK/T cell lymphoma as well as other peripheral T-cell lymphomas by IHC. Biopsies from 13 patients (5 from the United States, 8 from Korea) with nasal type NK/T cell lymphomas were evaluated by IHC. 12 of 13 (92%) patient samples expressed CS-1 with most cases showing a majority of cells positive. 46 PTCLs were also evaluated (including 9 AITL). Overall, 8/46 (17%) of the PTCL cases expressed CS-1. However, of the AITLs, 4 of 9 (44%) expressed CS-1. Conclusions: CS-1 is expressed on nearly all nasal type NK/T cell lymphomas and in a substantial proportion of AITLs. These results provide the rationale for exploring elotuzumab in the targeted treatment of NK/T-cell malignancies.

Gene Expression Profiling Identifies the JAK/STAT and NFκB Pathways to Be Important in Peripheral T-Cell Lymphomas and Natural-Killer T-Cell Lymphomas

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2658-2658
Author(s):  
Tiffany Tang ◽  
George Allen ◽  
Ghee Chong Koo ◽  
Kevin Tay ◽  
Daryl Tan ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Natural Killer T Cell ◽  
T Cell Lymphomas ◽  
Nk T Cells

Abstract Abstract 2658 Background: Peripheral T-cell lymphomas (PTCL) carry a poorer prognosis compared to their B-cell counterparts and the molecular pathogenesis of PTCL is still largely unknown. The aims of this study are to characterize the molecular signatures and identify signaling pathways involved in the different subsets of PTCL and NKTCL. Materials and Methods: RNA was extracted from tumors of 60 patients with newly diagnosed PTCL and NKTCL: 21 with angioimmunoblastic T-cell lymphoma (AITL), 12 anaplastic large-cell lymphoma (ALCL), 15 peripheral T-cell lymphoma not-otherwise-specified (PTCL-NOS) and 12 with natural-killer T-cell lymphoma (NKTCL). Comparisons were made using published gene expression data files of normal T and NK T-cells. Gene expression profiling was performed using the Affymetrix HG-U133 Plus 2.0 GeneChip platform. Results: The Affymetrix expression profiling distinguishes the 48 PTCL samples from normal T-cell controls (p<0.005). Similarly, the molecular signature of 12 NKTCL significantly differs from normal NK cells. The JAK/STAT pathway is significantly upregulated in AITL and a subset of PTCL-NOS compared to normal T cells and ALCL (p<0.005). [Figure 1] Pathways related to NFκB significantly distinguish PTCL from normal T-cells and it also distinguishes NKTCL from normal NK T-cells. Unsupervised hierarchical clustering by gene expression profiles is able to separate the subsets of PTCL (AILT, ALCL, NKTCL) in concordance with their immmunohistochemical diagnosis. PTCL-NOS however, are dispersed across the clusters reflecting its molecular heterogeneity. [Figure 2] Discussion: Gene expression profiling identifies distinct molecular pathways in PTCL. In particular, the JAK-STAT pathway is upregulated in AITL and the NFκB pathway is dysregulated in PTCL and NKCL. Our results suggest that targeting the key kinases in these pathways may be effective in the treatment for this subset of lymphomas with poor prognosis. Disclosures: Tan: Janssen: Honoraria, Research Funding; Celgene: Honoraria; Novartis: Research Funding.

scholarly journals Gene expression profiling identifies molecular subgroups among nodal peripheral T-cell lymphomas

Oncogene ◽  
2005 ◽  
Vol 25 (10) ◽  
pp. 1560-1570 ◽  
Author(s):  
B Ballester ◽  
O Ramuz ◽  
C Gisselbrecht ◽  
G Doucet ◽  
L Loï ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Molecular Subgroups ◽  
T Cell Lymphomas ◽  
Peripheral T Cell Lymphomas

scholarly journals Reproducing the molecular subclassification of peripheral T-cell lymphoma–NOS by immunohistochemistry

Blood ◽  
2019 ◽  
Vol 134 (24) ◽  
pp. 2159-2170 ◽  
Author(s):  
Catalina Amador ◽  
Timothy C. Greiner ◽  
Tayla B. Heavican ◽  
Lynette M. Smith ◽  
Karen Tatiana Galvis ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Prognostic Information ◽  
Peripheral T Cell Lymphoma ◽  
Not Otherwise Specified ◽  
T Cell Lymphomas ◽  
Molecular Separation ◽  
Peripheral T Cell Lymphomas

One-third of peripheral T-cell lymphomas are “not otherwise specified” (PTCL-NOS), but they have been subdivided into 2 subgroups based on gene expression profiling. Amador and colleagues generated an immunohistochemical algorithm that parallels the molecular separation of PTCL-NOS and provides useful prognostic information.

Biological Differences in Peripheral T-Cell Lymphomas Identified by DNA Microarrays.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3012-3012
Author(s):  
Beatriz Martinez-Delgado ◽  
Manisha Bahl ◽  
Marta Cuadros ◽  
Victoria Fernandez ◽  
Javier Benitez ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cells ◽  
T Cell ◽  
B Cell ◽  
Dna Microarrays ◽  
Expression Profiles ◽  
Resting Cells ◽  
T Cell Lymphomas ◽  
Infiltrating Cells ◽  
Peripheral T Cell Lymphomas

Abstract Peripheral T-cell lymphomas (PTCL) constitute a heterogeneous and aggressive group of tumors whose pathogenic alterations remain largely unknown. They show great morphologic, immunophenotypic and clinical differences. Expression profiling has been demonstrated to be a useful tool for the molecular classification of tumours. We used DNA microarrays (Affymetrics, Lymph_DX) to look for molecular differences in peripheral T-cell lymphomas. We analysed the expression of 19 pathologically confirmed PTCL (11 PTCL, unspecified (u) and 8 angioimmunoblastic, AILT). A time-course of stimulation with anti-CD3 and anti-CD28 was performed in CD4+ and CD8+ isolated peripheral blood lymphocytes, and the gene expression of tumors was compared with resting and stimulated normal T-cells. Cases of classical Hodgkin’s lymphoma, with which PTCL may be confused, were included. Gene expression of PTCL revealed several clusters of genes with biological significance showing differential expression within the tumors. We defined a “Cytotoxic Response” cluster characterized by the expression of cytotoxic molecules PRF1 and GZMB and GZMH, a “B-cell-related genes” cluster which included B-cell specific genes PAX5 or CD19, and an interesting “Resting-cells genes” cluster. These three clusters were negatively correlated with a “Proliferation” signature. On the other hand, the “Proliferation” signature significantly correlated with the expression of TNFRSF8 (CD30) (r=0.63, p=0.003) and the expression of CD3G (r=0.51, p=0.022). Other interesting genes were also found associated specifically to the proliferation of PTCL. Comparison between PTCLu and AILT showed differences in the expression of CD21 and other genes reflecting the higher presence of dendritic cells in AILT, and also revealed differences in expression of relevant chemokines, such us CXCL5, CXCL13 and CCL19. Intriguingly, compared with normal CD4 and CD8 T-cells, PTCL showed lower expression of most of the typical genes associated with T-cell biology, suggesting that PTCL often lose the common genetic program of T-cells. PTCL expression profiles are difficult to interpret due to the significant proportion of other infiltrating cells accompanying the tumor. Our results showed that microarrays are a helpful tool to dissect the PTCL expression profile, identifying those genes expressed by infiltrating cells and those expressed by tumor cells.

Activated oncogenic pathways and therapeutic targets in extranodal nasal-type NK/T cell lymphoma revealed by gene expression profiling

2011 ◽  
Vol 223 (4) ◽  
pp. 496-510 ◽  
Author(s):  
Siok-Bian Ng ◽  
Viknesvaran Selvarajan ◽  
Gaofeng Huang ◽  
Jianbiao Zhou ◽  
Andrew L Feldman ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Gene Expression Profiling ◽  
Expression Profiling ◽  
Cell Lymphoma ◽  
Therapeutic Targets ◽  
T Cell Lymphoma ◽  
Nasal Type ◽  
Oncogenic Pathways ◽  
Nk T Cell

Tumor Necrosis Factor-p Gene Expression and Its Relationship to the Clinical Features and Histopathogenesis of Peripheral T-Cell Lymphomas

1994 ◽  
Vol 16 (1-2) ◽  
pp. 125-133 ◽  
Author(s):  
Hirokazu Kato ◽  
Tetsuro Nagasaka ◽  
Atsushi Ichikawa ◽  
Tomohiro Kinoshita ◽  
Takashi Murate ◽  
...  
Keyword(s):  
Gene Expression ◽  
T Cell ◽  
Tumor Necrosis Factor ◽  
Clinical Features ◽  
Tumor Necrosis ◽  
P Gene ◽  
T Cell Lymphomas ◽  
Necrosis Factor ◽  
Peripheral T Cell Lymphomas

scholarly journals A Critical Role for Natural Killer T Cells in Immunosurveillance of Methylcholanthrene-induced Sarcomas

2002 ◽  
Vol 196 (1) ◽  
pp. 119-127 ◽  
Author(s):  
Nadine Y. Crowe ◽  
Mark J. Smyth ◽  
Dale I. Godfrey
Keyword(s):  
T Cells ◽  
T Cell ◽  
Natural Killer ◽  
Critical Role ◽  
Physiological Role ◽  
Cell Receptor ◽  
Interferon Γ ◽  
Tumor Rejection ◽  
Nk T Cells ◽  
Nk T Cell

Natural killer (NK) T cells initiate potent antitumor responses when stimulated by exogenous factors such as interleukin (IL)-12 or α-galactosylceramide (α-GalCer), however, it is not clear whether this reflects a physiological role for these cells in tumor immunity. Through adoptive transfer of NK T cells from wild-type to NK T cell–deficient (T cell receptor [TCR] Jα281−/−) mice, we demonstrate a critical role for NK T cells in immunosurveillance of methylcholanthrene (MCA)-induced fibrosarcomas, in the absence of exogenous stimulatory factors. Using the same approach with gene-targeted and/or antibody-depleted donor or recipient mice, we have shown that this effect depends on CD1d recognition and requires the additional involvement of both NK and CD8+ T cells. Interferon-γ production by both NK T cells and downstream, non-NK T cells, is essential for protection, and perforin production by effector cells, but not NK T cells, is also critical. The protective mechanisms in this more physiologically relevant system are distinct from those associated with α-GalCer–induced, NK T cell–mediated, tumor rejection. This study demonstrates that, in addition to their importance in tumor immunotherapy induced by IL-12 or α-GalCer, NK T cells can play a critical role in tumor immunosurveillance, at least against MCA-induced sarcomas, in the absence of exogenous stimulation.

scholarly journals Granzyme B-expressing peripheral T-cell lymphomas: neoplastic equivalents of activated cytotoxic T cells with preference for mucosa- associated lymphoid tissue localization

Blood ◽  
1994 ◽  
Vol 84 (11) ◽  
pp. 3785-3791 ◽  
Author(s):  
PC de Bruin ◽  
JA Kummer ◽  
P van der Valk ◽  
P van Heerde ◽  
PM Kluin ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Tumor Cells ◽  
Lymphoid Tissue ◽  
Cytotoxic T Cells ◽  
Granzyme B ◽  
Clinical Behavior ◽  
T Cell Lymphomas ◽  
Hodgkin's Lymphomas ◽  
Peripheral T Cell Lymphomas

T-cell non-Hodgkin's lymphomas can be considered the neoplastic equivalents of immunologically functional, site-restricted T lymphocytes. Little is known about the occurrence and clinical behavior of T-cell lymphomas that are the neoplastic equivalents of different functional T-cell subsets. Here, we investigated the prevalence, preferential site, immunophenotype, and clinical behavior of the neoplastic equivalents of activated cytotoxic T cells (CTLs) in a group of 140 nodal and extranodal T-cell lymphomas. Activated CTLs were shown immunohistochemically with a monoclonal antibody against granzyme B, a major constituent of the cytotoxic granules of activated T cells. Granzyme B-positive T-cell lymphomas were mainly found in mucosa- associated lymphoid tissue (MALT; nose, 63% of the cases; gastrointestinal tract, 46%; and lung, 33%). Granzyme B-positive cases with primary localization in MALT were more often associated with angioinvasion (P = .005), necrosis (P = .002), and histologic characteristics of celiac disease in adjacent mucosa not involved with lymphoma. Eosinophilia was more often observed in granzyme B-negative cases (P = .03). Most cases belonged to the pleomorphic medium- and large-cell group of the Kiel classification. CD30 expression was more often found in granzyme B-positive lymphomas of MALT (P = .04), whereas CD56 expression was exclusively found in nasal granzyme B-positive lymphomas. Immunophenotypically, most of the cases should be considered as neoplastic equivalents of activated CTLs based on the presence of T- cell markers on tumor cells. In two cases of nasal lymphoma, tumor cells probably were the neoplastic counterparts of natural killer cells. The prognosis of the granzyme B-positive gastrointestinal T-cell lymphomas was poor but did not differ from granzyme B-negative gastrointestinal T-cell lymphomas. This indicates that, in peripheral T- cell lymphomas, site of origin is more important as a prognostic parameter than derivation of activated CTLs.

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