scholarly journals Characterization of the humoral immune response to the EBV proteome in extranodal NK/T-cell lymphoma

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Zhiwei Liu ◽  
Yomani D. Sarathkumara ◽  
John K. C. Chan ◽  
Yok-Lam Kwong ◽  
Tai Hing Lam ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Antibody Response ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Igg Antibodies ◽  
Humoral Immune ◽  
Epithelial Origin ◽  
Iga Antibodies ◽  
Associated Tumors

AbstractExtranodal natural killer/T-cell lymphoma (NKTCL) is an aggressive malignancy that has been etiologically linked to Epstein-Barr virus (EBV) infection, with EBV gene transcripts identified in almost all cases. However, the humoral immune response to EBV in NKTCL patients has not been well characterized. We examined the antibody response to EBV in plasma samples from 51 NKTCL cases and 154 controls from Hong Kong and Taiwan who were part of the multi-center, hospital-based AsiaLymph case–control study. The EBV-directed serological response was characterized using a protein microarray that measured IgG and IgA antibodies against 202 protein sequences representing the entire EBV proteome. We analyzed 157 IgG antibodies and 127 IgA antibodies that fulfilled quality control requirements. Associations between EBV serology and NKTCL status were disproportionately observed for IgG rather than IgA antibodies. Nine anti-EBV IgG responses were significantly elevated in NKTCL cases compared with controls and had ORshighest vs. lowest tertile > 6.0 (Bonferroni-corrected P-values < 0.05). Among these nine elevated IgG responses in NKTCL patients, three IgG antibodies (all targeting EBNA3A) are novel and have not been observed for other EBV-associated tumors of B-cell or epithelial origin. IgG antibodies against EBNA1, which have consistently been elevated in other EBV-associated tumors, were not elevated in NKTCL cases. We characterize the antibody response against EBV for patients with NKTCL and identify IgG antibody responses against six distinct EBV proteins. Our findings suggest distinct serologic patterns of this NK/T-cell lymphoma compared with other EBV-associated tumors of B-cell or epithelial origin.

scholarly journals IgA Antibodies Against Gliadin and Tissue Transglutaminase in Dogs With Chronic Enteritis and Intestinal T-Cell Lymphoma

2017 ◽  
Vol 55 (1) ◽  
pp. 98-107 ◽  
Author(s):  
I. Matsumoto ◽  
K. Uchida ◽  
K. Nakashima ◽  
S. Hiyoshi ◽  
J. K. Chambers ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Tissue Transglutaminase ◽  
Cell Receptor ◽  
T Cell Lymphoma ◽  
Igg Antibodies ◽  
Intestinal Lymphoma ◽  
Serum Iga ◽  
Iga Antibodies ◽  
Clonality Analysis

Molecular clonality analysis of T-cell receptor (TCR) genes for diagnosing T-cell lymphoma is widely used in veterinary medicine. However, differentiating chronic enteritis (CE) from intestinal lymphoma is challenging because of the incompatibility between histopathologic and clonality analysis results. On the basis of findings that canine intestinal T-cell lymphoma and celiac disease share some common features, we conducted serologic examinations in combination with histopathologic and T-cell receptor clonality analyses in 48 dogs diagnosed with either CE or intestinal lymphoma. Immunoglobulin A (IgA) and immunoglobulin G (IgG) antibodies against gliadin and tissue transglutaminase (tTG) were quantitatively measured using ELISA. The conditions were classified according to the histopathologic diagnosis, clonality analysis, and combined histopathologic/clonality analysis. Histopathologic analysis showed that dogs with intestinal lymphoma were likely to have high levels of serum IgA antibodies against gliadin and tTG, and serum IgG antibodies against tTG. No correlation between the diagnosed groups and control group was observed in the results of the clonality analysis and histopathologic/clonality analysis. It is interesting that dogs with intestinal lymphoma had a higher serum IgA titer against gliadin and tTG than did dogs with CE. These results suggest an association between repetitive inflammatory stimulation by gliadin peptides and subsequent intestinal lymphoma in dogs.

Identification of Informative Gene Expression Signatures Indicative of Vorinostat (Suberoylanilide Hydroxamic Acid, SAHA) Exposure and Clinical Efficacy in Patients with Advanced Cutaneous T-Cell Lymphoma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4686-4686 ◽  
Author(s):  
Andrey Loboda ◽  
Valeria Fantin ◽  
Sophia Randolph ◽  
Justin L. Ricker ◽  
James S. Hardwick ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cell ◽  
Cell Lines ◽  
Lymphoid Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Gene Expression Signatures ◽  
Lymphoid Cell Lines

Abstract Vorinostat is a histone deacetylase inhibitor currently under evaluation in numerous oncology clinical trials. In a Phase IIb trial, oral vorinostat resulted in a 29.7% overall objective response rate in patients (pts) with advanced cutaneous T-cell lymphoma (CTCL) and had an acceptable safety profile. These results prompted efforts to identify gene expression patterns that could elucidate the molecular mechanism of action (MOA), assess exposure to vorinostat and enrich for pts who are likely to respond. In the Phase IIb trial, gene expression profiles were obtained from 24 predose and 30 postdose (2 hr postdose on Day 15) PBMC samples. The gene expression associated with Sezary burden was easily identified in predose samples and consistent with published results. Although the power of this dataset was limited for development of a predose predictor of response, we identified three biologically-relevant pathways that correlated with response and deserve further validation. First, we found a coherent cluster of proliferation/cell cycle genes to be associated with resistance to therapy. This may imply that tumor aggressiveness is an important factor for clinical response. Second, a set of antioxidant genes was upregulated in non-responders. The generation of reactive oxygen species (ROS) is a component of the vorinostat MOA and increased ROS scavenging ability may confer resistance. Finally, cytotoxic cell markers were upregulated in responders and may represent another factor associated with contribution of T and NK cells to response. Each of these 3 patterns, if confirmed, would allow for 20–50% responder enrichment. We observed robust postdose gene expression changes in which ~942 genes exhibited significant regulation (fold-change&gt;2, P&lt;0.01 by paired t-test between predose and postdose samples) regardless of clinical outcome. Treated samples were discriminated from untreated with 87.5% accuracy based on leave one-out-cross-validation (LOOCV) using penalized analysis of microarrays (PAM). To understand the biology, we projected the preclinical postdose signatures derived from acute postdose changes in a panel of human lymphoid cell lines. Overall, 85% of genes significantly regulated by vorinostat in lymphoid cell lines were also regulated in the same direction in PBMC samples from CTCL pts. Thus, most of the observed postdose changes result from acute vorinostat effects on gene expression. The average preclinical postdose signature can be used to predict proximal vorinostat exposure with 90% accuracy. Among the gene expression signatures observed in clinical samples but not in cell lines, two deserve special attention. First, proliferation-associated genes are downregulated postdose and are differentially expressed between responders and non-responders. It may serve as an efficacy biomarker and would allow for 80% accurate discrimination of responders from non-responders in postdose samples based on LOOCV using PAM. Second, cytokines and genes associated with the humoral immune response were downregulated at the same time genes and cytokines associated with a cytotoxic immune response were upregulated. Such changes in the Th1-Th2 balance may reflect part of the MOA for vorinostat, and may be particularly relevant to CTCL, a disease caused by Th2 type skin-homing lymphocytes. Further evaluation of vorinostat in CTCL, including additional validation of gene expression signatures that may predict response, is warranted.

scholarly journals Exosomes Isolated from Ascites of T-Cell Lymphoma-Bearing Mice Expressing Surface CD24 and HSP-90 Induce a Tumor-Specific Immune Response

2017 ◽  
Vol 8 ◽  
Author(s):  
Florencia Menay ◽  
Leticia Herschlik ◽  
Julieta De Toro ◽  
Federico Cocozza ◽  
Rodrigo Tsacalian ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Specific Immune Response ◽  
Hsp 90 ◽  
Tumor Specific Immune Response

scholarly journals The Immune Response to Class I-Associated Tumor-Specific Cutaneous T-Cell Lymphoma Antigens

1996 ◽  
Vol 107 (3) ◽  
pp. 392-397 ◽  
Author(s):  
Carole L. Berger ◽  
Nanci Wang ◽  
Inger Christensen ◽  
Jack Longley ◽  
Peter Heald ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Class I ◽  
Cutaneous T Cell Lymphoma

scholarly journals Role of Complement Receptor Type 2 and Endogenous Complement in the Humoral Immune Response to Conjugates of Complement C3d and Pneumococcal Serotype 14 Capsular Polysaccharide

2005 ◽  
Vol 73 (11) ◽  
pp. 7311-7316 ◽  
Author(s):  
Joyce K. Mitsuyoshi ◽  
Yong Hu ◽  
Samuel T. Test
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Antibody Response ◽  
Humoral Immune Response ◽  
Capsular Polysaccharide ◽  
Complement Receptor ◽  
Adjuvant Effect ◽  
Humoral Immune

ABSTRACT Conjugation of the complement fragment C3d to both T-cell-dependent (TD) protein and T-cell-independent type 2 (TI-2) polysaccharide antigens enhances the humoral immune response in mice immunized with either type of antigen. However, the ability of C3d-protein conjugates to enhance the antibody response in mice deficient in complement receptor types 1 and 2 (CR1 and CR2) has raised questions about the role of C3d-CR2 interactions in the adjuvant effect of C3d. In this study, we examined the role of CR2 binding and endogenous complement activation in the antibody response to conjugates of C3d and serotype 14 pneumococcal capsular polysaccharide (PPS14). To block binding of PPS14-C3d conjugates to CR2, mice were immunized with a mixture of vaccine and (CR2)2-immunoglobulin G1 (IgG1). Mice receiving (CR2)2-IgG1 at the time of primary immunization had a marked reduction in the primary anti-PPS14 antibody response but an enhanced secondary anti-PPS14 response, suggesting that C3d-CR2 interactions are required for the primary response but can have negative effects on the memory response. Further, compared with mice receiving PPS14-C3d having a high C3d/PPS14 ratio, mice immunized with PPS14-C3d with low C3d/PPS14 ratios had an enhanced secondary antibody response. Treatment of mice with cobra venom factor to deplete complement had insignificant effects on the antibody response to PPS14-C3d. Experiments with CBA/N xid mice confirmed that PPS14-C3d conjugates retain the characteristics of TI-2 rather than TD antigens. Thus, the adjuvant effect of C3d conjugated to PPS14 requires C3d-CR2 interactions, does not require activation of endogenous complement, and is not mediated by TD carrier effects.

scholarly journals T-cell lymphoma secondary to checkpoint inhibitor therapy

2020 ◽  
Vol 8 (1) ◽  
pp. e000104 ◽  
Author(s):  
Kartik Anand ◽  
Joe Ensor ◽  
Sai Ravi Pingali ◽  
Patrick Hwu ◽  
Madeleine Duvic ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Suppressor ◽  
Immune Checkpoint ◽  
Cell Lymphoma ◽  
Checkpoint Inhibitors ◽  
T Cell Lymphoma ◽  
T Cell Clones ◽  
Cell Clones ◽  
Epithelial Origin ◽  
Pharmacovigilance Database

BackgroundMurine model suggests programmed cell death-1 (PD-1), an immune checkpoint not only plays role in tumor escape but is also a tumor suppressor for T-cells. But until, no reports of secondary T-cell lymphoma postuse of immune checkpoint inhibitors (ICIs) has been reported. Herein, we present a hitherto unreported phenomenon of secondary T-cell lymphoma when PD-1 inhibitor was used in a patient diagnosed with a tumor of epithelial origin.Case reportA man in mid-70s presented with biopsy-proven metastatic tumor of epithelial origin. Patient received carboplatin in combination with paclitaxel for four cycles leading to partial remission. The patient was subsequently switched to pembrolizumab due to persistent disease in the mediastinum. After four cycles of PD-1 inhibitor, patient presented with progression of disease and was diagnosed with biopsy-proven peripheral T-cell lymphoma-not otherwise specified. Based on the reported tumor suppressor function of PD-1 in murine models, we hypothesized that the use of PD-1 inhibitor caused clonal proliferation of abnormal T-cell clone leading to T-cell lymphoma. T-cell receptor (TCR) sequencing was performed by TCRβ sequencing and T-cell clones from pre-ICI treatment specimen were compared with post-ICI treatment specimens. We show that one of the T-cell clones present in pre-ICI treatment specimen at a low frequency of had massive expansion to become most dominant clone in post-ICI treatment specimens leading to lymphoma. Moreover, targeted exome sequencing revealed a new TET2 mutation in the clone representing the lymphoma.Next, we retrospectively reviewed the Food and Drug Administration (FDA) Adverse Events Reporting System (FAERS), the pharmacovigilance database from 2012 to 2018 to find the reported incidence of this phenomenon and calculated the reporting OR (ROR) for disproportionality analysis for risk of T-cell lymphoma due to checkpoint inhibitors compared with other drugs. In FAERS, the incidence of T-cell lymphoma post-ICIs (pembrolizumab, nivolumab and ipilimumab) was found to be 0.02% with 17% mortality. The ROR probability of risk of T-cell lymphoma compared with other drugs in pharmacovigilance database was increased at 1.91.ConclusionsT-cell lymphoma is a rare sequela of ICIs with high mortality. Larger studies with long-term follow-up of patients receiving ICIs is needed.

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