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1. Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma

Author

Garcia-Marquez, Maria A., Thelen, Martin, Reinke, Sarah, Keller, Diandra, Wennhold, Kerstin, Lehmann, Jonas, Veldman, Johanna, Borchmann, Sven, Rosenwald, Andreas, Sasse, Stephanie, Diepstra, Arjan, Borchmann, Peter, Engert, Andreas, Klapper, Wolfram, von Bergwelt-Baildon, Michael, Bröckelmann, Paul J., and Schlößer, Hans A.

Published
2022
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4. Supplementary Data from Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Author

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

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

Author

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

Published
2023
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6. P031: CD4+ T cells in close proximity to Hodgkin-Reed Sternberg cells are antigen experienced, polyclonal and display an exhausted phenotype

Author

Veldman, Johanna, primary, Rodrigues Plaça., Jessica, additional, Chong, Lauren, additional, Terpstra, Martijn, additional, Mastik, Mirjam, additional, Van Kempen, Léon C., additional, Aoki, Tomohiro, additional, Steidl, Christian, additional, Van Den Berg, Anke, additional, Visser, Lydia, additional, and Diepstra, Arjan, additional

Published
2022
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7. CD4+ T cells in classical Hodgkin lymphoma express exhaustion associated transcription factors TOX and TOX2

Author

Veldman, Johanna, Rodrigues Plaça, Jessica, Chong, Lauren, Terpstra, Miente Martijn, Mastik, Mirjam, van Kempen, Léon C., Kok, Klaas, Aoki, Tomohiro, Steidl, Christian, van den Berg, Anke, Visser, Lydia, and Diepstra, Arjan

Subjects
CD4-Positive T-Lymphocytes, Dipeptidyl Peptidase 4, polyclonal, High Mobility Group Proteins, Hodgkin Disease, TOX, Hodgkin, HMGB Proteins, exhaustion, Humans, Lymph Nodes, Research Article, Original Research, CD26, Transcription Factors
Abstract

In classical Hodgkin lymphoma (cHL), the highly abundant CD4+ T cells in the vicinity of tumor cells are considered essential for tumor cell survival, but are ill-defined. Although they are activated, they consistently lack expression of activation marker CD26. In this study, we compared sorted CD4+CD26- and CD4+CD26+ T cells from cHL lymph node cell suspensions by RNA sequencing and T cell receptor variable gene segment usage analysis. This revealed that although CD4+CD26- T cells are antigen experienced, they have not clonally expanded. This may well be explained by the expression of exhaustion associated transcription factors TOX and TOX2, immune checkpoints PDCD1 and CD200, and chemokine CXCL13, which were amongst the 100 significantly enriched genes in comparison with the CD4+CD26+ T cells. Findings were validated in single-cell RNA sequencing data from an independent cohort. Interestingly, immunohistochemistry revealed predominant and high frequency of staining for TOX and TOX2 in the T cells attached to the tumor cells. In conclusion, the dominant CD4+CD26- T cell population in cHL is antigen experienced, polyclonal, and exhausted. This population is likely a main contributor to the very high response rates to immune checkpoint inhibitors in cHL.

Published
2022

8. Reverted exhaustion phenotype of circulating lymphocytes as immune correlate of anti-PD1 first-line treatment in Hodgkin lymphoma

Author

Garcia-Marquez, Maria A., primary, Thelen, Martin, additional, Reinke, Sarah, additional, Keller, Diandra, additional, Wennhold, Kerstin, additional, Lehmann, Jonas, additional, Veldman, Johanna, additional, Borchmann, Sven, additional, Rosenwald, Andreas, additional, Sasse, Stephanie, additional, Diepstra, Arjan, additional, Borchmann, Peter, additional, Engert, Andreas, additional, Klapper, Wolfram, additional, von Bergwelt-Baildon, Michael, additional, Bröckelmann, Paul J., additional, and Schlößer, Hans A., additional

Published
2021
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9. 9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial

Author

Gerhard‐Hartmann, Elena, primary, Goergen, Helen, additional, Bröckelmann, Paul J., additional, Mottok, Anja, additional, Steinmüller, Tabea, additional, Grund, Johanna, additional, Zamò, Alberto, additional, Ben‐Neriah, Susana, additional, Sasse, Stephanie, additional, Borchmann, Sven, additional, Fuchs, Michael, additional, Borchmann, Peter, additional, Reinke, Sarah, additional, Engert, Andreas, additional, Veldman, Johanna, additional, Diepstra, Arjan, additional, Klapper, Wolfram, additional, and Rosenwald, Andreas, additional

Published
2021
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10. The interplay between CD4 T cells and tumor cells in Hodgkin lymphoma:interactions and immune checkpoint blockade

Author

Veldman, Johanna and Veldman, Johanna

Abstract

Hodgkin lymphoma (HL) is a common malignancy in young adults. It is characterized by a minority of tumor cells surrounded by an abundant inflammatory infiltrate, which mainly consists of CD4+ T cells. The current treatment strategy has a high cure-rate, but often results in long-term treatment related adverse events. Therefore, new treatment options such as immune checkpoint blockade (ICB) are being explored. In this project we characterized CD4+ T cells and their interactions with tumor cells, with a specific focus on the role of CD4+ T cells in ICB therapy. We discovered that CD4+ T cells are weakly activated by T cell receptor (TCR)-HLA class II and CD2-CD58 interactions with the tumor cells. These T cells that are in close proximity to the tumor cells have been activated before (antigen experienced) and are diverse (polyclonal). In addition, they specifically express transcription factors TOX and TOX2 that are associated with T cell exhaustion and can be induced by chronic or repeated TCR stimulation. This suggests that Hodgkin tumor cells actively inhibit cells in their surrounding to promote tumor cell survival. We developed a long-term co-culture model and found that blocking PD-1 with nivolumab results in pronounced CD4+ T cell activation and proliferation, confirming the potential of this treatment in HL. In addition, we identified soluble PD-L1 as a promising biomarker in HL patients. In summary, our studies provide novel insights into the function of CD4+ T cells in HL biology and treatment responses. This may help improve immunotherapy in HL patients.

Published
2021

13. 9p24.1 alterations and programmed cell death 1 ligand 1 expression in early stage unfavourable classical Hodgkin lymphoma: an analysis from the German Hodgkin Study Group NIVAHL trial.

Author

Gerhard‐Hartmann, Elena, Goergen, Helen, Bröckelmann, Paul J., Mottok, Anja, Steinmüller, Tabea, Grund, Johanna, Zamò, Alberto, Ben‐Neriah, Susana, Sasse, Stephanie, Borchmann, Sven, Fuchs, Michael, Borchmann, Peter, Reinke, Sarah, Engert, Andreas, Veldman, Johanna, Diepstra, Arjan, Klapper, Wolfram, and Rosenwald, Andreas

Subjects
PROGRAMMED death-ligand 1, HODGKIN'S disease, MANTLE cell lymphoma, MAJOR histocompatibility complex
Abstract

Summary: High programmed cell death 1 ligand 1 (PD‐L1) protein expression and copy number alterations (CNAs) of the corresponding genomic locus 9p24.1 in Hodgkin‐ and Reed–Sternberg cells (HRSC) have been shown to be associated with favourable response to anti‐PD‐1 checkpoint inhibition in relapsed/refractory (r/r) classical Hodgkin lymphoma (cHL). In the present study, we investigated baseline 9p24.1 status as well as PD‐L1 and major histocompatibility complex (MHC) class I and II protein expression in 82 biopsies from patients with early stage unfavourable cHL treated with anti‐PD‐1‐based first‐line treatment in the German Hodgkin Study Group (GHSG) NIVAHL trial (ClinicalTrials.gov Identifier: NCT03004833). All evaluated specimens showed 9p24.1 CNA in HRSC to some extent, but with high intratumoral heterogeneity and an overall smaller range of alterations than reported in advanced‐stage or r/r cHL. All but two cases (97%) showed PD‐L1 expression by the tumour cells in variable amounts. While MHC‐I was rarely expressed in >50% of HRSC, MHC‐II expression in >50% of HRSC was found more frequently. No obvious impact of 9p24.1 CNA or PD‐L1 and MHC‐I/II expression on early response to the highly effective anti‐PD‐1‐based NIVAHL first‐line treatment was observed. Further studies evaluating an expanded panel of potential biomarkers are needed to optimally stratify anti‐PD‐1 first‐line cHL treatment. [ABSTRACT FROM AUTHOR]

Published
2022
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15. Single-Cell Transcriptome Analysis Reveals Disease-Defining T-cell Subsets in the Tumor Microenvironment of Classic Hodgkin Lymphoma

Author

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

Published
2020
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