Noncanonical effector functions of the T-memory–like T-PLL cell are shaped by cooperative TCL1A and TCR signaling
| Autor: | Michaela Kotrova, H J M Göx, Jan Dürig, Dimitrios Mougiakakos, J Makalowski, Prerana Wagle, T Neumann, Till Braun, Sebastian Oberbeck, Alexandra Schrader, Hinrich Abken, Monika Brüggemann, Marco Herling, Richard Moriggl, Martin Thelen, A Kondo Ados, Petra Mayer, Janine Altmüller, Tero Aittokallio, Sylvia Hartmann, Sebastian Newrzela, Linus Wahnschaffe, Thorsten Persigehl, Giuliano Crispatzu, Natali Pflug, Georg Hopfinger, Michael Hallek, Kathrin Warner, Alyssa Bouska, L. Varghese, M. L. Hansmann, Javeed Iqbal, J. von Jan, S. Pützer, Ingo Roeder, T A Müller, Gunter Rappl, M von Bergwelt-Baildon, S. Stilgenbauer, D Jungherz, Hans H. Diebner, Aleksandr Ianevski, Nicole Riet, Markus Chmielewski, Hans A. Schlößer |
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| Rok vydání: | 2020 |
| Předmět: |
T-Lymphocytes
medicine.medical_treatment Lymphocyte Immunology Cell Receptors Antigen T-Cell Medizin Biology Biochemistry Mice 03 medical and health sciences 0302 clinical medicine Proto-Oncogene Proteins medicine Animals Humans Prolymphocytic leukemia Receptor 030304 developmental biology Mice Knockout 0303 health sciences T-cell receptor NFAT Cell Biology Hematology medicine.disease Chimeric antigen receptor Cell biology medicine.anatomical_structure Cytokine 030220 oncology & carcinogenesis Leukemia Prolymphocytic T-Cell Immunologic Memory Signal Transduction |
| Zdroj: | Blood. 136:2786-2802 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood.2019003348 |
| Popis: | T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre)leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative-regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than-normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activation- and FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1Atg T cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling. |
| Databáze: | OpenAIRE |
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