Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling

Oberbeck, S.; Schrader, A.; Warner, K.; Jungherz, D.; Crispatzu, G.; von Jan, J.; Chmielewski, M.; Ianevski, A.; Diebner, H. H.; Mayer, P.; Ados, A. Kondo; Wahnschaffe, L.; Braun, T.; Müller, T. A.; Wagle, P.; Bouska, A.; Neumann, T.; Puetzer, S.; Varghese, L.; Pflug, N.; Thelen, M.; Makalowski, J.; Riet, N.; Goex, H. J. M.; Rappl, G.; Altmueller, J.; Kotrova, M.; Persigehl, T.; Hopfinger, G.; Hansmann, M. L.; Schloesser, H.; Stilgenbauer, S.; Duerig, J.; Mougiakakos, D.; Bergwelt-Baildon, M. von; Roeder, I; Hartmann, S.; Hallek, M.; Moriggl, R.; Brueggemann, M.; Aittokallio, T.; Iqbal, J.; Newrzela, S.; Abken, H. und Herling, M. (2020): Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling. In: Blood, Bd. 136, Nr. 24: S. 2786-2802

Abstract

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 activationand 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-hTCL1AtgT 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0006-4971
• Sprache: Englisch