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

Autor:in

Oberbeck, Sebastian; Schrader, Alexandra; Warner, Kathrin; Jungherz, Dennis; Crispatzu, Giuliano; von Jan, Jana; Chmielewski, Markus; Ianevski, Aleksandr; Diebner, Hans; Mayer, Petra; Ados, A. Kondo; Wahnschaffe, Linus; Braun, Till; Mueller, Tony Andreas; Wagle, P.; Bouska, Alyssa; Neumann, T.; Putzer, S.; Varghese, Lesley; Pflug, Natali; Thelen, Martin; Makalowski, Jennifer; Riet, Nicole; Goex, H. J. M.; Rappl, G; Altmuller, Janine; Kotrova, Michaela; Persigehl, Thorsten; Hopfinger, G.; Hansmann, Martin-Leo; Schloer, Hennes; Stilgenbauer, Stephan; Dueig, J.; MOUGIAKAKOS, DIMITRIOS; von Bergwelt-Baildon, Michael; Roeder, Ingo; Hartmann, Sylvia; Hallek, Michael; Moriggl, Richard; Brueggemann, Monika; Aittokallio, Tero; Iqbal, J.; Newrzela, Sebastian; Abken, H.; Herling, Marco

Abstrakt

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

Originalarbeit

DOI

10.1182/blood.2019003348

PubMed ID

MEDLINE:33301031