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

• Published in: Blood
• Main Authors: Oberbeck, Sebastian, Schrader, Alexandra, Warner, Kathrin, Jungherz, Dennis, Crispatzu, Giuliano, von Jan, Jana, Chmielewski, Markus, Ianevski, Aleksandr, Diebner, Hans H, Mayer, Petra, Kondo Ados, Aichatou, Wahnschaffe, Linus, Braun, Till, Müller, Tony A, Wagle, Prerana, Bouska, Alyssa, Neumann, Tom, Pützer, Sabine, Varghese, Lesley, Pflug, Natali, Thelen, Martin, Makalowski, Jennifer, Riet, Nicole, Göx, Hedwig Julia Maria, Rappl, Gunter, Altmüller, Janine, Kotrova, Michaela, Persigehl, Thorsten, Hopfinger, Georg, Hansmann, Martin L, Schlößer, Hans, Stilgenbauer, Stephan, Dürig, Jan, Mougiakakos, Dimitrios, von Bergwelt-Baildon, Michael, Roeder, Ingo, Hartmann, Sylvia, Hallek, Michael, Moriggl, Richard H, Brüggemann, Monika, Aittokallio, Tero, Iqbal, Javeed, Newrzela, Sebastian, Abken, Hinrich, Herling, Marco
• Format: Journal Article
• Language: English
• Published: United States 21-09-2020
• ISSN: 1528-0020

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 post-thymic T-cells. We assessed here 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 non-canonical 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 (e.g. 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 T-PLL's marked resistance to activation- and FAS-induced cell death. Enforced TCL1A enhanced phosho-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 CARs, 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 accumulation of death-resistant memory-type cells that utilize 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.