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CHRONIC LYMPHOCYTIC LEUKEMIA

Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors

Leukemia volume 37, pages 606–616 (2023) Cite this article

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Abstract

T-cell dysregulation in chronic lymphocytic leukemia (CLL) associates with low response rates to autologous T cell-based therapies. How CLL affects antigen-specific T-cell responses remains largely unknown. We investigated (epi)genetic and functional consequences of antigen-specific T-cell responses in presence of CLL in vitro and in an adoptive-transfer murine model. Already at steady-state, antigen-experienced patient-derived T cells were skewed towards short-lived effector cells (SLEC) at the expense of memory-precursor effector cells (MPEC). Stimulation of these T cells in vitro showed rapid induction of effector genes and suppression of key memory transcription factors only in presence of CLL cells, indicating epigenetic regulation. This was investigated in vivo by following antigen-specific responses of naïve OT-I CD8+ cells to mCMV-OVA in presence/absence of TCL1 B-cell leukemia. Presence of leukemia resulted in increased SLEC formation, with disturbed inflammatory cytokine production. Chromatin and transcriptome profiling revealed strong epigenetic modifications, leading to activation of an effector and silencing of a memory profile through presence of CLL cells. Secondary challenge in vivo confirmed dysfunctional memory responses by antigen-experienced OT-I cells generated in presence of CLL. Altogether, we show that presence of CLL induces a short-lived effector phenotype and impaired memory responses by epigenetic reprogramming during primary responses.

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Fig. 1: T cells from CLL patients are skewed towards effector cells and CLL cells induce an effector gene signature after in vitro activation.
The alternative text for this image may have been generated using AI.
Fig. 2: CLL-like disease induces skewing towards short-lived effector cells in a mouse model of acute infection.
The alternative text for this image may have been generated using AI.
Fig. 3: TCL1-derived OT-I cells show impaired cytokine production and degranulation upon restimulation.
The alternative text for this image may have been generated using AI.
Fig. 4: TCL1-derived OT-I cells are not exhausted, but have decreased expression of memory-related transcription factors.
The alternative text for this image may have been generated using AI.
Fig. 5: Transcriptional profile of OT-I cells is altered in TCL1 mice.
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Fig. 6: Chromatin accessibility of OT-I cells is altered in TCL1 mice.
The alternative text for this image may have been generated using AI.
Fig. 7: CLL-like disease induces impaired memory T-cell responses.
The alternative text for this image may have been generated using AI.

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Data availability

All data are available upon reasonable request. RNAseq and ATACseq raw and processed data have been deposited in the Gene Expression Omnibus (GEO) with accession number GSE185387. Code is available upon reasonable request.

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Acknowledgements

The authors would like to thank the Core Facility Genomics at the Amsterdam UMC for assistance in troubleshooting and sequencing the ATAC libraries and Dr. Maria Themeli for valuable scientific discussions. This work was supported by the Netherlands Organization for Scientific Research (NWO)/Netherlands Organization for Health Research and Development (ZonMw) VIDI grant (#91715337) and European Research Council (ERC) Consolidator grant (BOOTCAMP; 864815).

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Author notes

  1. These authors contributed equally: Anne W. J. Martens, Inga Kavazović, Fleur S. Peters, Arnon P. Kater.

Authors and Affiliations

  1. Department of Hematology, Amsterdam UMC, University of Amsterdam, Cancer Center Amsterdam, Lymphoma and Myeloma Center Amsterdam, Meibergdreef 9, Amsterdam, The Netherlands

    Anne W. J. Martens, Su Min Pack, Gerritje J. W. van der Windt, Fleur S. Peters & Arnon P. Kater

  2. Department of Experimental Immunology, Amsterdam UMC, University of Amsterdam, Amsterdam Infection & Immunity Institute, Meibergdreef 9, Amsterdam, The Netherlands

    Anne W. J. Martens, Su Min Pack, Eric Eldering, Gerritje J. W. van der Windt & Fleur S. Peters

  3. Department of Histology and Embryology, Faculty of Medicine, University of Rijeka, Rijeka, Croatia

    Inga Kavazović, Mia Krapić & Felix M. Wensveen

  4. Department of Immunology, Leiden University Medical Center, Leiden, The Netherlands

    Ramon Arens

  5. Department of Epidemiology and Data Science, Amsterdam UMC, University of Amsterdam, Amsterdam, The Netherlands

    Aldo Jongejan & Perry D. Moerland

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Contributions

AWJM, EE, GJWvdW, FMW, FSP, and APK designed research. AWJM, IK, MK, GJWvdW, FMW, FSP, and SMP performed research. AWJM, IK, AJ, PDM, FMW, FSP analyzed data. AWJM and FSP designed the figures. RA provided samples. AWJM, FSP, and APK wrote the paper. All authors reviewed and approved the manuscript.

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Correspondence to Arnon P. Kater.

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GJWvdW is an employee of Genmab. All other authors declare that they have no competing interests.

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Martens, A.W.J., Kavazović, I., Krapić, M. et al. Chronic lymphocytic leukemia presence impairs antigen-specific CD8+ T-cell responses through epigenetic reprogramming towards short-lived effectors. Leukemia 37, 606–616 (2023). https://doi.org/10.1038/s41375-023-01817-z

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