Noncanonical effector functions of the T-memory-like T-PLL cell are shaped by cooperative TCL1A and TCR signaling
Autor/innen
- S. Oberbeck
- A. Schrader
- K. Warner
- D. Jungherz
- G. Crispatzu
- J. von Jan
- M. Chmielewski
- A. Ianevski
- H.H. Diebner
- P. Mayer
- A. Kondo Ados
- L. Wahnschaffe
- T. Braun
- T.A. Müller
- P. Wagle
- A. Bouska
- T. Neumann
- S. Pützer
- L. Varghese
- N. Pflug
- M. Thelen
- J. Makalowski
- N. Riet
- H.J.M Göx
- G. Rappl
- J. Altmüller
- M. Kotrová
- T. Persigehl
- G. Hopfinger
- M.L. Hansmann
- H. Schlößer
- S. Stilgenbauer
- J. Dürig
- D. Mougiakakos
- M. von Bergwelt-Baildon
- I. Roeder
- S. Hartmann
- M. Hallek
- R. Moriggl
- M. Brüggemann
- T. Aittokallio
- J. Iqbal
- S. Newrzela
- H. Abken
- M. Herling
Journal
- Blood
Quellenangabe
- Blood 136 (24): 2786-2802
Zusammenfassung
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 Lck(pr)-hTCL1A(tg) 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.