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16 results on '"Adèle Telenius"'

1. Tumor-associated antigen PRAME exhibits dualistic functions that are targetable in diffuse large B cell lymphoma

Author

Katsuyoshi Takata, Lauren C. Chong, Daisuke Ennishi, Tomohiro Aoki, Michael Yu Li, Avinash Thakur, Shannon Healy, Elena Viganò, Tao Dao, Daniel Kwon, Gerben Duns, Julie S. Nielsen, Susana Ben-Neriah, Ethan Tse, Stacy S. Hung, Merrill Boyle, Sung Soo Mun, Christopher M. Bourne, Bruce Woolcock, Adèle Telenius, Makoto Kishida, Shinya Rai, Allen W. Zhang, Ali Bashashati, Saeed Saberi, Gianluca D’Antonio, Brad H. Nelson, Sohrab P. Shah, Pamela A. Hoodless, Ari M. Melnick, Randy D. Gascoyne, Joseph M. Connors, David A. Scheinberg, Wendy Béguelin, David W. Scott, and Christian Steidl

Subjects
Hematology, Oncology, Medicine
Abstract

PRAME is a prominent member of the cancer testis antigen family of proteins, which triggers autologous T cell–mediated immune responses. Integrative genomic analysis in diffuse large B cell lymphoma (DLBCL) uncovered recurrent and highly focal deletions of 22q11.22, including the PRAME gene, which were associated with poor outcome. PRAME-deleted tumors showed cytotoxic T cell immune escape and were associated with cold tumor microenvironments. In addition, PRAME downmodulation was strongly associated with somatic EZH2 Y641 mutations in DLBCL. In turn, PRC2-regulated genes were repressed in isogenic PRAME-KO lymphoma cell lines, and PRAME was found to directly interact with EZH2 as a negative regulator. EZH2 inhibition with EPZ-6438 abrogated these extrinsic and intrinsic effects, leading to PRAME expression and microenvironment restoration in vivo. Our data highlight multiple functions of PRAME during lymphomagenesis and provide a preclinical rationale for synergistic therapies combining epigenetic reprogramming with PRAME-targeted therapies.

Published
2022
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2. Genomic Alterations in CIITA Are Frequent in Primary Mediastinal Large B Cell Lymphoma and Are Associated with Diminished MHC Class II Expression

Author

Anja Mottok, Bruce Woolcock, Fong Chun Chan, King Mong Tong, Lauren Chong, Pedro Farinha, Adèle Telenius, Elizabeth Chavez, Suvan Ramchandani, Marie Drake, Merrill Boyle, Susana Ben-Neriah, David W. Scott, Lisa M. Rimsza, Reiner Siebert, Randy D. Gascoyne, and Christian Steidl

Subjects
Biology (General), QH301-705.5
Abstract

Primary mediastinal large B cell lymphoma (PMBCL) is an aggressive non-Hodgkin’s lymphoma, predominantly affecting young patients. We analyzed 45 primary PMBCL tumor biopsies and 3 PMBCL-derived cell lines for the presence of genetic alterations involving the major histocompatibility complex (MHC) class II transactivator CIITA and found frequent aberrations consisting of structural genomic rearrangements, missense, nonsense, and frame-shift mutations (53% of primary tumor biopsies and all cell lines). We also detected intron 1 mutations in 47% of the cases, and detailed sequence analysis strongly suggests AID-mediated aberrant somatic hypermutation as the mutational mechanism. Furthermore, we demonstrate that genomic lesions in CIITA result in decreased protein expression and reduction of MHC class II surface expression, creating an immune privilege phenotype in PMBCL. In summary, we establish CIITA alterations as a common mechanism of immune escape through reduction of MHC class II expression in PMBCL, with potential implications for future treatments targeting microenvironment-related biology.

Published
2015
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3. Supplementary Table S8-9 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

Prognostic values of MHC expression

Published
2023
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4. Supplementary Table S11 and 15 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

IHC antibodies and cell line information

Published
2023
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5. Supplementary Methods and Figures from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

Supplementary Methods, Figures and Legends

Published
2023
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6. Supplementary Table S4-5 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

Genetic backgrounds of MHC deficient cases

Published
2023
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7. Supplementary Table S12-14 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

Genetic analysis in the MHC-I/II double-positive cases

Published
2023
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8. Data from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

We performed a genomic, transcriptomic, and immunophenotypic study of 347 patients with diffuse large B-cell lymphoma (DLBCL) to uncover the molecular basis underlying acquired deficiency of MHC expression. Low MHC-II expression defines tumors originating from the centroblast-rich dark zone of the germinal center (GC) that was associated with inferior prognosis. MHC-II–deficient tumors were characterized by somatically acquired gene mutations reducing MHC-II expression and a lower amount of tumor-infiltrating lymphocytes. In particular, we demonstrated a strong enrichment of EZH2 mutations in both MHC-I– and MHC-II–negative primary lymphomas, and observed reduced MHC expression and T-cell infiltrates in murine lymphoma models expressing mutant Ezh2Y641. Of clinical relevance, EZH2 inhibitors significantly restored MHC expression in EZH2-mutated human DLBCL cell lines. Hence, our findings suggest a tumor progression model of acquired immune escape in GC-derived lymphomas and pave the way for development of complementary therapeutic approaches combining immunotherapy with epigenetic reprogramming.Significance:We demonstrate how MHC-deficient lymphoid tumors evolve in a cell-of-origin–specific context. Specifically, EZH2 mutations were identified as a genetic mechanism underlying acquired MHC deficiency. The paradigmatic restoration of MHC expression by EZH2 inhibitors provides the rationale for synergistic therapies combining immunotherapies with epigenetic reprogramming to enhance tumor recognition and elimination.See related commentary by Velcheti et al., p. 472.This article is highlighted in the In This Issue feature, p. 453

Published
2023
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9. Supplementary Table S10 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

EZH2 mutation data

Published
2023
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10. Supplementary Table S6-7 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

Gene expression analyses of clinical samples

Published
2023
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11. Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Author

Christian Steidl, Sohrab P. Shah, Akil Merchant, Anja Mottok, Brad H. Nelson, Gerald Krystal, David W. Scott, Kerry J. Savage, Andrew P. Weng, Pedro Farinha, Jiarui Ding, Saeed Saberi, Jubin Kim, Allen W. Zhang, Johanna Veldman, Talia Goodyear, Daniel Kos, Chanel Ghesquiere, Shannon Healy, Michael Y. Li, Adèle Telenius, Bruce W. Woolcock, Elena Viganò, Vivian Lam, Tomoko Miyata-Takata, Xuehai Wang, Michael Nissen, Elizabeth A. Chavez, Anthony Colombo, Monirath Hav, Katy Milne, Katsuyoshi Takata, Lauren C. Chong, and Tomohiro Aoki

Abstract

Hodgkin lymphoma is characterized by an extensively dominant tumor microenvironment (TME) composed of different types of noncancerous immune cells with rare malignant cells. Characterization of the cellular components and their spatial relationship is crucial to understanding cross-talk and therapeutic targeting in the TME. We performed single-cell RNA sequencing of more than 127,000 cells from 22 Hodgkin lymphoma tissue specimens and 5 reactive lymph nodes, profiling for the first time the phenotype of the Hodgkin lymphoma–specific immune microenvironment at single-cell resolution. Single-cell expression profiling identified a novel Hodgkin lymphoma–associated subset of T cells with prominent expression of the inhibitory receptor LAG3, and functional analyses established this LAG3+ T-cell population as a mediator of immunosuppression. Multiplexed spatial assessment of immune cells in the microenvironment also revealed increased LAG3+ T cells in the direct vicinity of MHC class II–deficient tumor cells. Our findings provide novel insights into TME biology and suggest new approaches to immune-checkpoint targeting in Hodgkin lymphoma.Significance:We provide detailed functional and spatial characteristics of immune cells in classic Hodgkin lymphoma at single-cell resolution. Specifically, we identified a regulatory T-cell–like immunosuppressive subset of LAG3+ T cells contributing to the immune-escape phenotype. Our insights aid in the development of novel biomarkers and combination treatment strategies targeting immune checkpoints.See related commentary by Fisher and Oh, p. 342.This article is highlighted in the In This Issue feature, p. 327

Published
2023
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12. Supplementary Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Author

Christian Steidl, Sohrab P. Shah, Akil Merchant, Anja Mottok, Brad H. Nelson, Gerald Krystal, David W. Scott, Kerry J. Savage, Andrew P. Weng, Pedro Farinha, Jiarui Ding, Saeed Saberi, Jubin Kim, Allen W. Zhang, Johanna Veldman, Talia Goodyear, Daniel Kos, Chanel Ghesquiere, Shannon Healy, Michael Y. Li, Adèle Telenius, Bruce W. Woolcock, Elena Viganò, Vivian Lam, Tomoko Miyata-Takata, Xuehai Wang, Michael Nissen, Elizabeth A. Chavez, Anthony Colombo, Monirath Hav, Katy Milne, Katsuyoshi Takata, Lauren C. Chong, and Tomohiro Aoki

Abstract

Supplementary Methods, Supplementary Figures 1-19, Supplementary References

Published
2023
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13. Supplementary Table S1-3 from Molecular and Genetic Characterization of MHC Deficiency Identifies EZH2 as Therapeutic Target for Enhancing Immune Recognition

Author

Christian Steidl, Ari M. Melnick, David W. Scott, Randy D. Gascoyne, Joseph M. Connors, Sohrab P. Shah, Marco A. Marra, Ryan D. Morin, Laurie H. Sehn, Kerry J. Savage, Robert Kridel, Matt Teater, Daniel Lai, Adèle Telenius, Bruce W. Woolcock, Susana Ben-Neriah, Barbara Meissner, Merrill Boyle, Saeed Saberi, Ali Bashashati, Pedro Farinha, Anja Mottok, Gerben Duns, Wendy Béguelin, Katsuyoshi Takata, and Daisuke Ennishi

Abstract

MHC expression status in the cohort

Published
2023
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15. Distinct Molecular Subtypes of Classic Hodgkin Lymphoma Identified By Comprehensive Noninvasive Profiling

Author

Stefan K. Alig, Mohammad Shahrokh Esfahani, Michael Y. Li, Ragini Malika Adams, Andrea Garofalo, Michael C. Jin, Mari Olsen, Adèle Telenius, Brian Sworder, Joseph Schroers-Martin, Daniel A. King, Cédric Rossi, Andre Schultz, Karan R. Kathuria, Chih Long Liu, Valeria Spina, Lieselot Buedts, Jamie E. Flerlage, Sharon M. Castellino, Ranjana H. Advani, Davide Rossi, Ryan C. Lynch, Olivier Casasnovas, David M. Kurtz, Lianna J. Marks, Michael P. Link, Marc André, Peter Vandenberghe, Christian Steidl, Maximilian Diehn, and Ash A. Alizadeh

Subjects
Immunology, Cell Biology, Hematology, Biochemistry
Published
2022
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16. Histological Transformation and Progression in Follicular Lymphoma: A Clonal Evolution Study.

Author

Robert Kridel, Fong Chun Chan, Anja Mottok, Merrill Boyle, Pedro Farinha, King Tan, Barbara Meissner, Ali Bashashati, Andrew McPherson, Andrew Roth, Karey Shumansky, Damian Yap, Susana Ben-Neriah, Jamie Rosner, Maia A Smith, Cydney Nielsen, Eva Giné, Adele Telenius, Daisuke Ennishi, Andrew Mungall, Richard Moore, Ryan D Morin, Nathalie A Johnson, Laurie H Sehn, Thomas Tousseyn, Ahmet Dogan, Joseph M Connors, David W Scott, Christian Steidl, Marco A Marra, Randy D Gascoyne, and Sohrab P Shah

Subjects
Medicine
Abstract

BackgroundFollicular lymphoma (FL) is an indolent, yet incurable B cell malignancy. A subset of patients experience an increased mortality rate driven by two distinct clinical end points: histological transformation and early progression after immunochemotherapy. The nature of tumor clonal dynamics leading to these clinical end points is poorly understood, and previously determined genetic alterations do not explain the majority of transformed cases or accurately predict early progressive disease. We contend that detailed knowledge of the expansion patterns of specific cell populations plus their associated mutations would provide insight into therapeutic strategies and disease biology over the time course of FL clinical histories.Methods and findingsUsing a combination of whole genome sequencing, targeted deep sequencing, and digital droplet PCR on matched diagnostic and relapse specimens, we deciphered the constituent clonal populations in 15 transformation cases and 6 progression cases, and measured the change in clonal population abundance over time. We observed widely divergent patterns of clonal dynamics in transformed cases relative to progressed cases. Transformation specimens were generally composed of clones that were rare or absent in diagnostic specimens, consistent with dramatic clonal expansions that came to dominate the transformation specimens. This pattern was independent of time to transformation and treatment modality. By contrast, early progression specimens were composed of clones that were already present in the diagnostic specimens and exhibited only moderate clonal dynamics, even in the presence of immunochemotherapy. Analysis of somatic mutations impacting 94 genes was undertaken in an extension cohort consisting of 395 samples from 277 patients in order to decipher disrupted biology in the two clinical end points. We found 12 genes that were more commonly mutated in transformed samples than in the preceding FL tumors, including TP53, B2M, CCND3, GNA13, S1PR2, and P2RY8. Moreover, ten genes were more commonly mutated in diagnostic specimens of patients with early progression, including TP53, BTG1, MKI67, and XBP1.ConclusionsOur results illuminate contrasting modes of evolution shaping the clinical histories of transformation and progression. They have implications for interpretation of evolutionary dynamics in the context of treatment-induced selective pressures, and indicate that transformation and progression will require different clinical management strategies.

Published
2016
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